血管紧张素Ⅱ受体基因多态性与肾上腺醛固酮腺瘤发病风险及预后的相关性研究
|
摘要
背景
原发性醛固酮增多症(Primary aldosteronism, PA)是由于醛固酮(Aldosterone,ALD)自主高分泌引起不同程度的血浆肾素抑制、水钠潴留、高血压或者低血钾为主要表现的临床症候群。PA是引起继发性高血压的最常见病因之一,PA引起的高血压占高血压人群的比例已超过10%,在抵抗性(顽固性)高血压患者中更是高达20%左右。PA最常见的亚型是肾上腺醛固酮腺瘤(Aldosterone-Producing Adenoma,APA)和特发性醛固酮增多症(Idiopathic Hyperaldosteronism,IHA),分别占PA患者的60%和30%左右。然而,APA和IHA的发病机制目前仍尚不清楚。一般认为IHA多采用药物治疗,APA行外科手术治疗,虽然APA的手术治疗能够有效控制醛固酮的高分泌和治愈大部分患者的低血钾,但是只能使50%患者血压完全恢复正常,仍有部分APA患者术后血压控制不佳。
肾素-血管紧张素系统(Renin-angiotensin system, RAS)是机体血压、水盐平衡以及醛固酮合成与释放的最主要的调节因素,这些调节功能似乎均是通过血管紧张素Ⅱ与其最主要的两个受体亚型——血管紧张素Ⅱ1型受体(AngiotensinⅡType 1 Receptor, AT1R)和血管紧张素Ⅱ2型受体(AngiotensinⅡType 2 Receptor, AT2R)的结合来介导的。在肾上腺皮质,肾素、血管紧张素原和AT1R/AT2R共同构成了局部RAS调节,不依赖于循环RAS调节来调控ALD的合成与分泌。AT2R有对抗AT1R介导的血管紧张素Ⅱ效应,如对抗AT1R介导的细胞增殖、缩血管效应、心血管的纤维化等。越来越多的研究发现AT1R、AT2R基因多态性和高血压、心肌病、脑中风等心脑血管疾病相关,AT1R基因多态性还和女性乳腺癌发病有关。AT1R、AT2R基因由于遗传或者环境因素的影响,可能导致其表达量的紊乱或者活性的变化,使它们的生理调节功能失调,从而导致多种疾病的发生。因此针对APA的特点,我们将从AT1R、AT2R基因相关位点多态性入手,研究AT1R、AT2R基因多态性与APA发病风险、基因表达以及APA临床预后的相关性,从而进一步了解APA的发病机制,指导APA的临床预判和治疗。
方法
1.用DNeasy Blood & Tissue DNA提取试剂盒提取148例APA患者的组织DNA及192例正常人群外周血DNA,-20℃保存。
2.选取50例新鲜APA组织和50例正常肾上腺组织,采用Trizol法提取总RNA,RT-PCR半定量分析AT1R和AT2R mRNA在APA组织和正常肾上腺组织中的表达差异。免疫组织化学染色检测AT1R和AT2R的蛋白表达情况。进一步用实时荧光定量RT-PCR检测不同组织中AT2R mRNA表达水平。
3.根据公共SNP数据库(http://www.hapmap.org/和http://ncbi.nlm.nih.gov/SNP/)以及相关文献的报道,选择AT1R和AT2R基因中频数≥0.05,且与血压调控、心血管疾病密切相关的4个SNP位点,包括AT1R基因的rs5182、rs5186两个SNP位点,和AT2R基因的rs5194、rsl403543两个SNP位点。
4.采用MGB-Taqman探针法对AT1R、AT2R基因的4个多态性位点分别进行基因型检测。
5.收集148例APA患者术前血压、生化指标、肿瘤直径等临床资料,并进行术后血压恢复情况随访。术后6个月BP< 140/90mmHg,且不需任何抗高血压药物者认为术后BP正常,否则认为术后持续性高血压。
6.SNPassoc R语言统计包中,分析各SNP位点基因型分布是否符合Hardy-Weinberg平衡(HWE)(P>0.05认为符合HWE)。应用SPSS16.0和R statistics program 2.7.0软件包分析AT1R、AT2R基因多态性与APA的发病、基因表达水平、以及术后血压恢复的相关性。以优势比(odds ratio, OR)和95%可信区间(confidenceinterval, CI)来表示相对危险度。P<0.05或95%可信区间(CI)不包含1.0认为有统计学意义。
结果
1.多态性位点基因型检测及分布：4个双等位基因多态性位点包括rs5182、rs5186、rs5194和rsl403543均成功检测。各位点基因型分布均符合Hardy-Weinberg平衡(e>0.05)。
2.AT1R、AT2R基因多态性与APA发病危险相关性：正常组和疾病组人群的性别分布、年龄和身体质量指数(BMI)无统计学差异(P>0.05)。4个SNPs中仅发现rs5194多态性和单位点APA发病危险相关。等位基因频率分析发现, APA组AT2R基因rs5194位点A等位基因频率(0.49)要高于正常人群组(0.35)(χ2=12.08,P=0.001),差异有统计学意义。以rs5194纯合子基因型GG为参照,纯合子基因型AA和杂合子基因型GA的APA发病风险均增高(OR=2.66,95%CI=1.45-4.87和OR=1.67,95%CI=1.02-2.74)。rs5194位点单核苷酸多态性在不同的遗传模型,包括显性模型、隐性模型以及加性模型中均与APA发病相关联。(OR=1.94,95%CI=1.23-3.06,P=0.003；OR=2.01,95%CI=1.17-3.45,P=0.01；和OR=1.64,95%CI=1.21-2.20,P=0.001)
3.AT1R、AT2R基因多态性与APA患者术后血压恢复的关系：随访了128例APA患者,其中术后BP正常者72例,术后持续性高血压者56例。两组在性别、年龄、BMI、肿瘤大小、术前高血压水平以及持续时间没有明显差异,而术后持续性高血压组术前所需降压药≥3种的患者要明显多于术后血压正常组,分别为39／56(69.82%)和26／72(36.11%),P=0.000。随访患者4个位点基因型分布均符合Hardy-Weinberg平衡(P>0.05)。单个位点分析发现,4个SNP位点中只有AT2R基因rs1403543(G／A)位点多态性和术后持续性高血压相关联,其纯合子GG基因型患者要比AA基因型或GA基因型患者术后出现持续性高血压的危险性高(OR=5.00,95%CI=1.31-19.15,P=0.01)。
4.血管紧张素Ⅱ受体基因多态性与其表达的关系：半定量分析发现AT1R mRNA在APA组织、瘤旁组织以及正常肾上腺组织中的表达无明显差异(P>0.05)；AT2RmRNA在APA组织中的表达低于正常肾上腺组织(P<0.05)。而且免疫组织化学染色分析发现,AT1R蛋白在腺瘤和正常肾上腺组织中均为阳性表达,AT2R蛋白在腺瘤组织中的表达明显下调。针对AT2R的实时荧光定量PCR定量分析也进一步证实了AT2RmRNA在APA组织中的表达低于正常肾上腺组织(P<0.05)。Rs5194含A等位基因的基因型(AA+GA) AT2R mRNA表达量约为纯合子GG基因型的1／8,在APA组织和正常肾上腺组织均有显著差异性(P=0.000)。未发现rs1403543不同基因型之间AT2RmRNA表达量的差异。
结论
1.AT2R基因单核苷酸多态性与APA发病危险以及APA患者术后血压的恢复与否相关联,对AT2R基因多态性检测可能对预测APA的发病危险提供有用的遗传信息,AT2R基因多态性也可能成为一个预判APA临床预后的遗传标记。
2.AT2R基因多态性可能通过下调AT2R mRNA的表达量,从而导致APA的发病,其确切分子机制还有待我们下一步深入研究。
3.与高血压密切相的AT1R基因的遗传变异和APA的发病危险或者临床表型可能没有相关性。
Introduction
Primary aldosteronism (PA) is caused by autonomous aldosterone hypersecretion in the absence of excess angiotensin leading to sodium retention and potassium excretion with various degrees of hypertension, hypokalemia and renin suppression. A large body of evidence has established that PA is one of the most common form of secondary hypertension, with a prevalence of>10% among unselected hypertensives and 20% among patients with resistant hypertension. The most common clinical subtypes of PA are aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA), which respectively accounts for 60% and 30% of PA patients. But the pathogenesis of APA or IHA still remains unclear. Mineralocorticoid receptor antagonists are recommended for IHA while APA usually needs surgical treatment (unilateral laparoscopic adrenalectomy). Surgery has been reported to abolish aldosterone hypersecretion and hypokalemia in most patients with APA, however, it cures hypertension in only one in every two cases. Part of patients with APA show postoperative persist hypertension.
The renin-angiotensin system (RAS) mediates several classic physiologies including body water and electrolyte homeostasis, blood pressure and generation of aldosterone. These functions appear to be mediated by the angiotensinⅡtype 1 and type 2 receptors (AT1R, AT2R) subtype system. In the adrenal cortex, renin, angiotensinogen, AT1R and AT2R together compose a local angiotensinⅡsystem regulated independently from the circulating RAS. AT2R appear to modulate tissue development and repair and to counterbalance the effects of the angiotensinⅡmediated by AT1R, including cell growth, vasoconstriction, cardiovascular fibrosis and so on. More and more studies suggest that polymorphisims in AT1R and AT2R genes are associated with hypertension, myocardial disease, stroke even femal breast cancer. Genetic or environmental factors potentially disturb the expression and activity of AT1R and AT2R, which may lead to disorders of their regulating function. On the basis of the above hypothesis, this study aims to investigate the associations of polymorphisms in AT1R/AT2R genes with the risk and postoperative prognosis of APA.
Methods
1. Genomic DNA was extracted by DNeasy Blood & Tissue DNA purification Kit from adenoma tissues of 148 APA patients and peripheral blood samples of 192 normal people as controls, and stored at-20℃.
2. Total RNA was extracted by Trizol from 50 cases of APA tissues and 50 normal adrenal tissues. The mRNA expression of AT1R and AT2R were examined through reverse transcriptase polymerase chain reaction (RT-PCR). The difference of AT1R/AT2R protein expression in APA and normal adrenal tissue was detected by immunohistochemical stain. Fluorescent quantitative real-time RCR was performed for the quantitative determination of AT2R mRNA expression.
3. Based on the public SNP databases (http://ncbi.nlm.nih.gov/SNP/and http://www.hapmap.org/) and published documents, four DNA polymorphism loci at AT1R/AT2R genes with a minor allele frequency≥0.05 and potential associations between their variations and hypertension or other cardiovascular disease were selected for our study. The 4 SNPs are rs5182 (573T/C) in exon 4, rs5186 (1166A/C) in 3'untranslated region (UTR) of AT1R gene and rs5194 (2274G/A) in 3'-UTR, rs1403543 (1675G/A) in intron 1 of AT2R gene.
4. Genotypes of the 4 SNP loci were detected by MGB-Taqman probe method.
5. Collect clinical data of the 148 APA patients, including preoperative BP, biochemical index and tumor size et al. The postoperative recovery of BP was followed up since 6 months after surgery. Patients were categorized as cured if they had no hypertension [defined as systolic blood pressure (SBP)<140 mm Hg and diastolic blood pressure (DBP) <90 mm Hg] and were not taking any antihypertensive medications, or they were categorized as having persistent hypertension.
6. Hardy-Weinberg equilibrium (HWE) of each polymorphism locus was determined by SNPassoc in R statistics program 2.7.0 software package (P>0.05 was considered that genotype distribution was in accordance with HWE). SPSS 16.0 and R statistics program were used for statistical analyzing the associations between polymorphisms in AT1R/AT2R genes and the risk of APA、postoperative recovery of BP and gene expression. Odds ratio (OR) and 95% confidence interval (CI) were calculated to show the relative risk。A P value <0.05 or odds ratio (OR) 1.00 is not in the range of 95% CI implicating statistical significant.
Results
1. Genotyping and distribution:Four SNP loci including rs5182, rs5186, rs5194 and rs1403543 at AT1R/AT2R genes were successfully detected. The distribution of genotypes of each locus was in accordance with Hardy-Weinberg Equilibrium (HWE) in APA and control group (P> 0.05).
2. Association between AT1R/AT2R gene polymorphisms and risk of APA:The sex, age and BMI of APA patients and normal peoples have no significant difference (P>0.05). Of the 4 loci, rs5194 SNP at AT2R gene was most significantly associated with APA in additive (OR=1.64,95%CI=1.21-2.20, P=0.001), dominant (OR=1.94,95%CI=1.23-3.06, P=0.003), and recessive model (OR=2.01,95%CI=1.17-3.45, P=0.01). The A allele frequency at rs5194 was significantly higher in APA group (0.49) than that in normal controls group (0.35) (χ2=12.08, P=0.001). Homozygotic genotype GG and heterozygotic genotype GA had an increased risk of APA compared to AA genotype (OR=2.66,95% CI=1.45-4.87; OR=1.67,95% CI=1.02-2.74).
3. Association between AT1R/AT2R gene polymorphisms and postoperative BP recovery of APA:Total of 128 APA patients have been followed up including 72 patients with idea postoperative BP control and 56 with postoperative persist hypertension. Except for amounts of antihypertensive medications for preoperative BP control, no significant differences were found in sex, age, BMI, tumor size, preoperative BP level and duration of hypertension between the two groups. The distribution of genotypes of each locus was in accordance with Hardy-Weinberg Equilibrium (HWE) in the above two groups (P> 0.05). Of the 4 SNPs, only rs 1403543 locus in AT2R gene was found associated with postoperative persist hypertension of APA patients. APA patients with homozygotic genotype GG had an increased risk of persist postoperative hypertension compared to patients with AA or GA genotype (OR=5.00,95% CI=1.31-19.15, P=0.01).
4. Relationship between polymorphisms in angiotensinⅡreceptor gene and its expression variation:Semiquantitative analysis found that mRNA expression of AT1R in adenoma and normal tissues of adrenal gland showed no apparent differences (P>0.05). But the mRNA expression of AT2R in APA tissue is lower than that in normal adrenal gland tissues (P<0.05). Further more, immunohistochemical stain showed AT2R protein expression was also down regulated in APA tissue compared with normal adrenal tissue. But the AT1R protein was positive expressed in both APA and normal adrenal tissue. Fluorescent quantitative real-time RCR further verified the result of down regulation of AT2R mRNA expression in APA tissue. Alle A in rs5194 was associated with down regulation of AT2R mRNA expression. The ratio of AT2R mRNA expression in AA and GA genotypes to GG genotype is about 1/8 (P=0.000). No statistical significance was found in AT2R mRNA expression between different genotypes of rs1403543 locus.
Conclusions
1. DNA polymorphisms within AT2R gene were associated with the risk of APA and postoperative BP recovery of APA patients. Detection of polymorphisms within AT2R gene may provide useful genetic information for prognosing the risk of APA, anl also could be a predictor for APA patients with postoperative persist hypertension.
2. DNA polymorphisms within AT2R gene may be able to down regulate AT2R mRNA expression, which could be a potential pathogenesis of APA. But the exact molecular mechanism needs to be further investigated.
3. Genetic variants within AT1R gene, which is closely relative to hypertension disease, maybe not accociated with the risk and clinical phenotype of APA.
原发性醛固酮增多症(Primary aldosteronism, PA)是由于醛固酮(Aldosterone,ALD)自主高分泌引起不同程度的血浆肾素抑制、水钠潴留、高血压或者低血钾为主要表现的临床症候群。PA是引起继发性高血压的最常见病因之一,PA引起的高血压占高血压人群的比例已超过10%,在抵抗性(顽固性)高血压患者中更是高达20%左右。PA最常见的亚型是肾上腺醛固酮腺瘤(Aldosterone-Producing Adenoma,APA)和特发性醛固酮增多症(Idiopathic Hyperaldosteronism,IHA),分别占PA患者的60%和30%左右。然而,APA和IHA的发病机制目前仍尚不清楚。一般认为IHA多采用药物治疗,APA行外科手术治疗,虽然APA的手术治疗能够有效控制醛固酮的高分泌和治愈大部分患者的低血钾,但是只能使50%患者血压完全恢复正常,仍有部分APA患者术后血压控制不佳。
肾素-血管紧张素系统(Renin-angiotensin system, RAS)是机体血压、水盐平衡以及醛固酮合成与释放的最主要的调节因素,这些调节功能似乎均是通过血管紧张素Ⅱ与其最主要的两个受体亚型——血管紧张素Ⅱ1型受体(AngiotensinⅡType 1 Receptor, AT1R)和血管紧张素Ⅱ2型受体(AngiotensinⅡType 2 Receptor, AT2R)的结合来介导的。在肾上腺皮质,肾素、血管紧张素原和AT1R/AT2R共同构成了局部RAS调节,不依赖于循环RAS调节来调控ALD的合成与分泌。AT2R有对抗AT1R介导的血管紧张素Ⅱ效应,如对抗AT1R介导的细胞增殖、缩血管效应、心血管的纤维化等。越来越多的研究发现AT1R、AT2R基因多态性和高血压、心肌病、脑中风等心脑血管疾病相关,AT1R基因多态性还和女性乳腺癌发病有关。AT1R、AT2R基因由于遗传或者环境因素的影响,可能导致其表达量的紊乱或者活性的变化,使它们的生理调节功能失调,从而导致多种疾病的发生。因此针对APA的特点,我们将从AT1R、AT2R基因相关位点多态性入手,研究AT1R、AT2R基因多态性与APA发病风险、基因表达以及APA临床预后的相关性,从而进一步了解APA的发病机制,指导APA的临床预判和治疗。
方法
1.用DNeasy Blood & Tissue DNA提取试剂盒提取148例APA患者的组织DNA及192例正常人群外周血DNA,-20℃保存。
2.选取50例新鲜APA组织和50例正常肾上腺组织,采用Trizol法提取总RNA,RT-PCR半定量分析AT1R和AT2R mRNA在APA组织和正常肾上腺组织中的表达差异。免疫组织化学染色检测AT1R和AT2R的蛋白表达情况。进一步用实时荧光定量RT-PCR检测不同组织中AT2R mRNA表达水平。
3.根据公共SNP数据库(http://www.hapmap.org/和http://ncbi.nlm.nih.gov/SNP/)以及相关文献的报道,选择AT1R和AT2R基因中频数≥0.05,且与血压调控、心血管疾病密切相关的4个SNP位点,包括AT1R基因的rs5182、rs5186两个SNP位点,和AT2R基因的rs5194、rsl403543两个SNP位点。
4.采用MGB-Taqman探针法对AT1R、AT2R基因的4个多态性位点分别进行基因型检测。
5.收集148例APA患者术前血压、生化指标、肿瘤直径等临床资料,并进行术后血压恢复情况随访。术后6个月BP< 140/90mmHg,且不需任何抗高血压药物者认为术后BP正常,否则认为术后持续性高血压。
6.SNPassoc R语言统计包中,分析各SNP位点基因型分布是否符合Hardy-Weinberg平衡(HWE)(P>0.05认为符合HWE)。应用SPSS16.0和R statistics program 2.7.0软件包分析AT1R、AT2R基因多态性与APA的发病、基因表达水平、以及术后血压恢复的相关性。以优势比(odds ratio, OR)和95%可信区间(confidenceinterval, CI)来表示相对危险度。P<0.05或95%可信区间(CI)不包含1.0认为有统计学意义。
结果
1.多态性位点基因型检测及分布：4个双等位基因多态性位点包括rs5182、rs5186、rs5194和rsl403543均成功检测。各位点基因型分布均符合Hardy-Weinberg平衡(e>0.05)。
2.AT1R、AT2R基因多态性与APA发病危险相关性：正常组和疾病组人群的性别分布、年龄和身体质量指数(BMI)无统计学差异(P>0.05)。4个SNPs中仅发现rs5194多态性和单位点APA发病危险相关。等位基因频率分析发现, APA组AT2R基因rs5194位点A等位基因频率(0.49)要高于正常人群组(0.35)(χ2=12.08,P=0.001),差异有统计学意义。以rs5194纯合子基因型GG为参照,纯合子基因型AA和杂合子基因型GA的APA发病风险均增高(OR=2.66,95%CI=1.45-4.87和OR=1.67,95%CI=1.02-2.74)。rs5194位点单核苷酸多态性在不同的遗传模型,包括显性模型、隐性模型以及加性模型中均与APA发病相关联。(OR=1.94,95%CI=1.23-3.06,P=0.003；OR=2.01,95%CI=1.17-3.45,P=0.01；和OR=1.64,95%CI=1.21-2.20,P=0.001)
3.AT1R、AT2R基因多态性与APA患者术后血压恢复的关系：随访了128例APA患者,其中术后BP正常者72例,术后持续性高血压者56例。两组在性别、年龄、BMI、肿瘤大小、术前高血压水平以及持续时间没有明显差异,而术后持续性高血压组术前所需降压药≥3种的患者要明显多于术后血压正常组,分别为39／56(69.82%)和26／72(36.11%),P=0.000。随访患者4个位点基因型分布均符合Hardy-Weinberg平衡(P>0.05)。单个位点分析发现,4个SNP位点中只有AT2R基因rs1403543(G／A)位点多态性和术后持续性高血压相关联,其纯合子GG基因型患者要比AA基因型或GA基因型患者术后出现持续性高血压的危险性高(OR=5.00,95%CI=1.31-19.15,P=0.01)。
4.血管紧张素Ⅱ受体基因多态性与其表达的关系：半定量分析发现AT1R mRNA在APA组织、瘤旁组织以及正常肾上腺组织中的表达无明显差异(P>0.05)；AT2RmRNA在APA组织中的表达低于正常肾上腺组织(P<0.05)。而且免疫组织化学染色分析发现,AT1R蛋白在腺瘤和正常肾上腺组织中均为阳性表达,AT2R蛋白在腺瘤组织中的表达明显下调。针对AT2R的实时荧光定量PCR定量分析也进一步证实了AT2RmRNA在APA组织中的表达低于正常肾上腺组织(P<0.05)。Rs5194含A等位基因的基因型(AA+GA) AT2R mRNA表达量约为纯合子GG基因型的1／8,在APA组织和正常肾上腺组织均有显著差异性(P=0.000)。未发现rs1403543不同基因型之间AT2RmRNA表达量的差异。
结论
1.AT2R基因单核苷酸多态性与APA发病危险以及APA患者术后血压的恢复与否相关联,对AT2R基因多态性检测可能对预测APA的发病危险提供有用的遗传信息,AT2R基因多态性也可能成为一个预判APA临床预后的遗传标记。
2.AT2R基因多态性可能通过下调AT2R mRNA的表达量,从而导致APA的发病,其确切分子机制还有待我们下一步深入研究。
3.与高血压密切相的AT1R基因的遗传变异和APA的发病危险或者临床表型可能没有相关性。
Introduction
Primary aldosteronism (PA) is caused by autonomous aldosterone hypersecretion in the absence of excess angiotensin leading to sodium retention and potassium excretion with various degrees of hypertension, hypokalemia and renin suppression. A large body of evidence has established that PA is one of the most common form of secondary hypertension, with a prevalence of>10% among unselected hypertensives and 20% among patients with resistant hypertension. The most common clinical subtypes of PA are aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA), which respectively accounts for 60% and 30% of PA patients. But the pathogenesis of APA or IHA still remains unclear. Mineralocorticoid receptor antagonists are recommended for IHA while APA usually needs surgical treatment (unilateral laparoscopic adrenalectomy). Surgery has been reported to abolish aldosterone hypersecretion and hypokalemia in most patients with APA, however, it cures hypertension in only one in every two cases. Part of patients with APA show postoperative persist hypertension.
The renin-angiotensin system (RAS) mediates several classic physiologies including body water and electrolyte homeostasis, blood pressure and generation of aldosterone. These functions appear to be mediated by the angiotensinⅡtype 1 and type 2 receptors (AT1R, AT2R) subtype system. In the adrenal cortex, renin, angiotensinogen, AT1R and AT2R together compose a local angiotensinⅡsystem regulated independently from the circulating RAS. AT2R appear to modulate tissue development and repair and to counterbalance the effects of the angiotensinⅡmediated by AT1R, including cell growth, vasoconstriction, cardiovascular fibrosis and so on. More and more studies suggest that polymorphisims in AT1R and AT2R genes are associated with hypertension, myocardial disease, stroke even femal breast cancer. Genetic or environmental factors potentially disturb the expression and activity of AT1R and AT2R, which may lead to disorders of their regulating function. On the basis of the above hypothesis, this study aims to investigate the associations of polymorphisms in AT1R/AT2R genes with the risk and postoperative prognosis of APA.
Methods
1. Genomic DNA was extracted by DNeasy Blood & Tissue DNA purification Kit from adenoma tissues of 148 APA patients and peripheral blood samples of 192 normal people as controls, and stored at-20℃.
2. Total RNA was extracted by Trizol from 50 cases of APA tissues and 50 normal adrenal tissues. The mRNA expression of AT1R and AT2R were examined through reverse transcriptase polymerase chain reaction (RT-PCR). The difference of AT1R/AT2R protein expression in APA and normal adrenal tissue was detected by immunohistochemical stain. Fluorescent quantitative real-time RCR was performed for the quantitative determination of AT2R mRNA expression.
3. Based on the public SNP databases (http://ncbi.nlm.nih.gov/SNP/and http://www.hapmap.org/) and published documents, four DNA polymorphism loci at AT1R/AT2R genes with a minor allele frequency≥0.05 and potential associations between their variations and hypertension or other cardiovascular disease were selected for our study. The 4 SNPs are rs5182 (573T/C) in exon 4, rs5186 (1166A/C) in 3'untranslated region (UTR) of AT1R gene and rs5194 (2274G/A) in 3'-UTR, rs1403543 (1675G/A) in intron 1 of AT2R gene.
4. Genotypes of the 4 SNP loci were detected by MGB-Taqman probe method.
5. Collect clinical data of the 148 APA patients, including preoperative BP, biochemical index and tumor size et al. The postoperative recovery of BP was followed up since 6 months after surgery. Patients were categorized as cured if they had no hypertension [defined as systolic blood pressure (SBP)<140 mm Hg and diastolic blood pressure (DBP) <90 mm Hg] and were not taking any antihypertensive medications, or they were categorized as having persistent hypertension.
6. Hardy-Weinberg equilibrium (HWE) of each polymorphism locus was determined by SNPassoc in R statistics program 2.7.0 software package (P>0.05 was considered that genotype distribution was in accordance with HWE). SPSS 16.0 and R statistics program were used for statistical analyzing the associations between polymorphisms in AT1R/AT2R genes and the risk of APA、postoperative recovery of BP and gene expression. Odds ratio (OR) and 95% confidence interval (CI) were calculated to show the relative risk。A P value <0.05 or odds ratio (OR) 1.00 is not in the range of 95% CI implicating statistical significant.
Results
1. Genotyping and distribution:Four SNP loci including rs5182, rs5186, rs5194 and rs1403543 at AT1R/AT2R genes were successfully detected. The distribution of genotypes of each locus was in accordance with Hardy-Weinberg Equilibrium (HWE) in APA and control group (P> 0.05).
2. Association between AT1R/AT2R gene polymorphisms and risk of APA:The sex, age and BMI of APA patients and normal peoples have no significant difference (P>0.05). Of the 4 loci, rs5194 SNP at AT2R gene was most significantly associated with APA in additive (OR=1.64,95%CI=1.21-2.20, P=0.001), dominant (OR=1.94,95%CI=1.23-3.06, P=0.003), and recessive model (OR=2.01,95%CI=1.17-3.45, P=0.01). The A allele frequency at rs5194 was significantly higher in APA group (0.49) than that in normal controls group (0.35) (χ2=12.08, P=0.001). Homozygotic genotype GG and heterozygotic genotype GA had an increased risk of APA compared to AA genotype (OR=2.66,95% CI=1.45-4.87; OR=1.67,95% CI=1.02-2.74).
3. Association between AT1R/AT2R gene polymorphisms and postoperative BP recovery of APA:Total of 128 APA patients have been followed up including 72 patients with idea postoperative BP control and 56 with postoperative persist hypertension. Except for amounts of antihypertensive medications for preoperative BP control, no significant differences were found in sex, age, BMI, tumor size, preoperative BP level and duration of hypertension between the two groups. The distribution of genotypes of each locus was in accordance with Hardy-Weinberg Equilibrium (HWE) in the above two groups (P> 0.05). Of the 4 SNPs, only rs 1403543 locus in AT2R gene was found associated with postoperative persist hypertension of APA patients. APA patients with homozygotic genotype GG had an increased risk of persist postoperative hypertension compared to patients with AA or GA genotype (OR=5.00,95% CI=1.31-19.15, P=0.01).
4. Relationship between polymorphisms in angiotensinⅡreceptor gene and its expression variation:Semiquantitative analysis found that mRNA expression of AT1R in adenoma and normal tissues of adrenal gland showed no apparent differences (P>0.05). But the mRNA expression of AT2R in APA tissue is lower than that in normal adrenal gland tissues (P<0.05). Further more, immunohistochemical stain showed AT2R protein expression was also down regulated in APA tissue compared with normal adrenal tissue. But the AT1R protein was positive expressed in both APA and normal adrenal tissue. Fluorescent quantitative real-time RCR further verified the result of down regulation of AT2R mRNA expression in APA tissue. Alle A in rs5194 was associated with down regulation of AT2R mRNA expression. The ratio of AT2R mRNA expression in AA and GA genotypes to GG genotype is about 1/8 (P=0.000). No statistical significance was found in AT2R mRNA expression between different genotypes of rs1403543 locus.
Conclusions
1. DNA polymorphisms within AT2R gene were associated with the risk of APA and postoperative BP recovery of APA patients. Detection of polymorphisms within AT2R gene may provide useful genetic information for prognosing the risk of APA, anl also could be a predictor for APA patients with postoperative persist hypertension.
2. DNA polymorphisms within AT2R gene may be able to down regulate AT2R mRNA expression, which could be a potential pathogenesis of APA. But the exact molecular mechanism needs to be further investigated.
3. Genetic variants within AT1R gene, which is closely relative to hypertension disease, maybe not accociated with the risk and clinical phenotype of APA.
引文
1. Conn JW. Presidential address. Ⅰ. Painting background. Ⅱ. Primary aldosteronism, a new clinical syndrome. J Lab Clin Med,1955,45:3-17.
2. Kaplan NM. Hypokalemia in the hypertensive patient, with observations on the incidence of primary aldosteronism. Ann Intern Med,1967,66:1079-90.
3. Lund JO, Nielsen MD and Giese J. Prevalence of primary aldosteronism. Acta Med Scand Suppl,1981,646:54-7.
4. Sinclair AM, Isles CG, Brown I et al. Secondary hypertension in a blood pressure clinic. Arch Intern Med,1987,147:1289-93.
5. Conn JW, Cohen EL, Rovner DR et al. Normokalemic Primary Aldosteronism. a Detectable Cause of Curable "Essential" Hypertension. Jama,1965,193:200-6.
6. Mosso L, Carvajal C, Gonzalez A et al. Primary aldosteronism and hypertensive disease. Hypertension,2003,42:161-5.
7. Schwartz GL and Turner ST. Screening for primary aldosteronism in essential hypertension:diagnostic accuracy of the ratio of plasma aldosterone concentration to plasma renin activity. Clin Chem,2005,51:386-94.
8. Gordon RD, Stowasser M, Tunny TJ et al. High incidence of primary aldosteronism in 199 patients referred with hypertension. Clin Exp Pharmacol Physiol,1994,21: 315-8.
9. Plouin PF, Amar L and Chatellier G. Trends in the prevalence of primary aldosteronism, aldosterone-producing adenomas, and surgically correctable aldosterone-dependent hypertension. Nephrol Dial Transplant,2004,19:774-7.
10. Loh KC, Koay ES, Khaw MC et al. Prevalence of primary aldosteronism among Asian hypertensive patients in Singapore. J Clin Endocrinol Metab,2000,85:2854-9.
11. Gallay BJ, Ahmad S, Xu L et al. Screening for primary aldosteronism without discontinuing hypertensive medications:plasma aldosterone-renin ratio. Am J Kidney Dis,2001,37:699-705.
12. Eide IK, Torjesen PA, Drolsum A et al. Low-renin status in therapy-resistant hypertension:a clue to efficient treatment. J Hypertens,2004,22:2217-26.
13. Strauch B, Zelinka T, Hampf M et al. Prevalence of primary hyperaldosteronism in moderate to severe hypertension in the Central Europe region. J Hum Hypertens, 2003,17:349-52.
14. Milliez P, Girerd X, Plouin PF et al. Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol,2005,45:1243-8.
15. Stewart PM. Mineralocorticoid hypertension. Lancet,1999,353:1341-7.
16. Giacchetti G, Mulatero P, Mantero F et al. Primary aldosteronism, a major form of low renin hypertension:from screening to diagnosis. Trends Endocrinol Metab,2008, 19:104-8.
17. Plouin PF, Rossignol P and Amar L. Selection of patients for surgery for primary aldosteronism. Clin Exp Pharmacol Physiol,2008,35:522-5.
18. Meyer A, Brabant G and Behrend M. Long-term follow-up after adrenalectomy for primary aldosteronism. World J Surg,2005,29:155-9.
19. Lumachi F, Ermani M, Basso SM et al. Long-term results of adrenalectomy in patients with aldosterone-producing adenomas:multivariate analysis of factors affecting unresolved hypertension and review of the literature. Am Surg,2005,71: 864-9.
20. Harris DA, Au-Yong I, Basnyat PS et al. Review of surgical management of aldosterone secreting tumours of the adrenal cortex. Eur J Surg Oncol,2003,29: 467-74.
21. Fallo F, Pistorello M, Pedini F et al. In vitro evidence for local generation of renin and angiotensin Ⅱ/Ⅲ immunoreactivity by the human adrenal gland. Acta Endocrinol (Copenh),1991,125:319-30.
22. de Gasparo M, Catt KJ, Inagami T et al. International union of pharmacology. XXIII. The angiotensin Ⅱ receptors. Pharmacol Rev,2000,52:415-72.
23. Gard PR. The role of angiotensin Ⅱ in cognition and behaviour. Eur J Pharmacol, 2002,438:1-14.
24. McKinley MJ, Albiston AL, Allen AM et al. The brain renin-angiotensin system: location and physiological roles. Int J Biochem Cell Biol,2003,35:901-18.
25. Thomas WG and Mendelsohn FA. Angiotensin receptors:form and function and distribution. Int J Biochem Cell Biol,2003,35:774-9.
26. Vinson GP, Ho MM and Puddefoot JR. The distribution of angiotensin II type 1 receptors, and the tissue renin-angiotensin systems. Mol Med Today,1995,1:35-9.
27. Aguilera G Factors controlling steroid biosynthesis in the zona glomerulosa of the adrenal. J Steroid Biochem Mol Biol,1993,45:147-51.
28. Hilbers U, Peters J, Bornstein SR et al. Local renin-angiotensin system is involved in K+-induced aldosterone secretion from human adrenocortical NCI-H295 cells. Hypertension,1999,33:1025-30.
29. Belloni AS, Andreis PG, Macchi V et al. Distribution and functional significance of angiotensin-Ⅱ AT1-and AT2-receptor subtypes in the rat adrenal gland. Endocr Res, 1998,24:1-15.
30. Nakajima M, Hutchinson HQ Fujinaga M et al. The angiotensin Ⅱ type 2 (AT2) receptor antagonizes the growth effects of the AT1 receptor:gain-of-function study using gene transfer. Proc Natl Acad Sci USA,1995,92:10663-7.
31. Inagami T, Eguchi S, Numaguchi K et al. Cross-talk between angiotensin Ⅱ receptors and the tyrosine kinases and phosphatases. J Am Soc Nephrol,1999,10 Suppl 11: S57-61.
32. Widdop RE, Jones ES, Hannan RE et al. Angiotensin AT2 receptors:cardiovascular hope or hype? Br J Pharmacol,2003,140:809-24.
33. Wu L, Iwai M, Nakagami H et al. Effect of angiotensin Ⅱ type 1 receptor blockade on cardiac remodeling in angiotensin Ⅱtype 2 receptor null mice. Arterioscler Thromb Vasc Biol,2002,22:49-54.
34. Xu J, Carretero OA, Liu YH et al. Role of AT2 receptors in the cardioprotective effect of AT1 antagonists in mice. Hypertension,2002,40:244-50.
35. Brede M, Roell W, Ritter O et al. Cardiac hypertrophy is associated with decreased eNOS expression in angiotensin AT2 receptor-deficient mice. Hypertension,2003,42: 1177-82.
36. Oishi Y, Ozono R, Yano Y et al. Cardioprotective role of AT2 receptor in postinfarction left ventricular remodeling. Hypertension,2003,41:814-8.
37. Bonnardeaux A, Davies E, Jeunemaitre X et al. Angiotensin Ⅱ type 1 receptor gene polymorphisms in human essential hypertension. Hypertension,1994,24:63-9.
38. Kainulainen K, Perola M, Terwilliger J et al. Evidence for involvement of the type 1 angiotensin Ⅱ receptor locus in essential hypertension. Hypertension,1999,33:844-9.
39. Diez J, Laviades C, Orbe J et al. The A1166C polymorphism of the AT1 receptor gene is associated with collagen type Ⅰ synthesis and myocardial stiffness in hypertensives. J Hypertens,2003,21:2085-92.
40. Koh WP, Yuan JM, Van Den Berg D et al. Polymorphisms in angiotensin Ⅱ type 1 receptor and angiotensin I-converting enzyme genes and breast cancer risk among Chinese women in Singapore. Carcinogenesis,2005,26:459-64.
41. Zhang Y, Zhang KX, Wang GL et al. Angiotensin Ⅱ type 2 receptor gene polymorphisms and essential hypertension. Acta Pharmacol Sin,2003,24:1089-93.
42. Alfakih K, Maqbool A, Sivananthan M et al. Left ventricle mass index and the common, functional, X-linked angiotensin Ⅱ type-2 receptor gene polymorphism (-1332 G/A) in patients with systemic hypertension. Hypertension,2004,43:1189-94.
43. Schmieder RE, Erdmann J, Delles C et al. Effect of the angiotensin Ⅱ type 2-receptor gene (+1675 G/A) on left ventricular structure in humans. J Am Coll Cardiol,2001, 37:175-82.
1. Milliez P, Girerd X, Plouin PF et al. Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol, 2005,45:1243-8.
2. Stewart PM. Mineralocorticoid hypertension. Lancet,1999,353:1341-7.
3. Enberg U, Volpe C, Hoog A et al. Postoperative differentiation between unilateral adrenal adenoma and bilateral adrenal hyperplasia in primary aldosteronism by mRNA expression of the gene CYP11B2. Eur J Endocrinol,2004,151:73-85.
4. Zwermann O, Beuschlein F, Lalli E et al. Clinical and molecular evidence for DAX-1 inhibition of steroidogenic factor-1-dependent ACTH receptor gene expression. Eur J Endocrinol,2005,152:769-76.
5. de Fraipont F, El Atifi M, Cherradi N et al. Gene expression profiling of human adrenocortical tumors using complementary deoxyribonucleic Acid microarrays identifies several candidate genes as markers of malignancy. J Clin Endocrinol Metab,2005,90:1819-29.
6. Reincke M, Beuschlein F, Slawik M et al. Molecular adrenocortical tumourigenesis. Eur J Clin Invest,2000,30 Suppl 3:63-8.
7. Sidhu S, Gicquel C, Bambach CP et al. Clinical and molecular aspects of adrenocortical tumourigenesis. ANZ J Surg,2003,73:727-38.
8. Fallo F, Pistorello M, Pedini F et al. In vitro evidence for local generation of renin and angiotensin Ⅱ/Ⅲ immunoreactivity by the human adrenal gland. Acta Endocrinol (Copenh),1991,125:319-30.
9. de Gasparo M, Catt KJ, Inagami T et al. International union of pharmacology. ⅩⅩⅢ. The angiotensin Ⅱ receptors. Pharmacol Rev,2000,52:415-72.
10. Gard PR. The role of angiotensin Ⅱ in cognition and behaviour. Eur J Pharmacol, 2002,438:1-14.
11. McKinley MJ, Albiston AL, Allen AM et al. The brain renin-angiotensin system: location and physiological roles. Int J Biochem Cell Biol,2003,35:901-18.
12. Thomas WG and Mendelsohn FA. Angiotensin receptors:form and function and distribution. Int J Biochem Cell Biol,2003,35:774-9.
13. Vinson GP, Ho MM and Puddefoot JR. The distribution of angiotensin Ⅱ type 1 receptors, and the tissue renin-angiotensin systems. Mol Med Today,1995,1:35-9.
14. Inagami T, Eguchi S, Numaguchi K et al. Cross-talk between angiotensin Ⅱ receptors and the tyrosine kinases and phosphatases. J Am Soc Nephrol,1999,10 Suppl11:S57-61.
15. Widdop RE, Jones ES, Hannan RE et al. Angiotensin AT2 receptors:cardiovascular hope or hype? Br J Pharmacol,2003,140:809-24.
16. Xu J, Carretero OA, Liu YH et al. Role of AT2 receptors in the cardioprotective effect of AT1 antagonists in mice. Hypertension,2002,40:244-50.
17. Oishi Y, Ozono R, Yano Y et al. Cardioprotective role of AT2 receptor in postinfarction left ventricular remodeling. Hypertension,2003,41:814-8.
18. Schmieder RE, Erdmann J, Delles C et al. Effect of the angiotensin Ⅱ type 2-receptor gene (+1675 G/A) on left ventricular structure in humans. J Am Coll Cardiol,2001,37:175-82.
19. Alfakih K, Maqbool A, Sivananthan M et al. Left ventricle mass index and the common, functional, X-linked angiotensin Ⅱ type-2 receptor gene polymorphism (-1332 G/A) in patients with systemic hypertension. Hypertension,2004,43: 1189-94.
20. Koh WP, Yuan JM, Van Den Berg D et al. Polymorphisms in angiotensin Ⅱ type 1 receptor and angiotensin I-converting enzyme genes and breast cancer risk among Chinese women in Singapore. Carcinogenesis,2005,26:459-64.
21. Bielinska M, Parviainen H, Kiiveri S et al. Origin and Molecular Pathology of Adrenocortical Neoplasms. Vet Pathol,2009.
22. Gicquel C, Bertagna X and Le Bouc Y. Recent advances in the pathogenesis of adrenocortical tumours. Eur J Endocrinol,1995,133:133-44.
23. Reincke M. Mutations in adrenocortical tumors. Horm Metab Res,1998,30: 447-55.
24. Bertherat J, Groussin L, Sandrini F et al. Molecular and functional analysis of PRKAR1A and its locus (17q22-24) in sporadic adrenocortical tumors:17q losses, somatic mutations, and protein kinase A expression and activity. Cancer Res,2003, 63:5308-19.
25. Tissier F, Cavard C, Groussin L et al. Mutations of beta-catenin in adrenocortical tumors:activation of the Wnt signaling pathway is a frequent event in both benign and malignant adrenocortical tumors. Cancer Res,2005,65:7622-7.
26. Stratakis CA. Genetics of adrenocortical tumors:gatekeepers, landscapers and conductors in symphony. Trends Endocrinol Metab,2003,14:404-10.
27. Honda T, Nakamura T, Saito Y et al. Combined primary aldosteronism and preclinical Cushing's syndrome:an unusual case presentation of adrenal adenoma. Hypertens Res,2001,24:723-6.
28. Lenzini L, Seccia TM, Aldighieri E et al. Heterogeneity of aldosterone-producing adenomas revealed by a whole transcriptome analysis. Hypertension,2007,50: 1106-13.
29. Assie G, Auzan C, Gasc JM et al. Steroidogenesis in aldosterone-producing adenoma revisited by transcriptome analysis. J Clin Endocrinol Metab,2005,90: 6638-49.
30. Saner-Amigh K, Mayhew BA, Mantero F et al. Elevated expression of luteinizing hormone receptor in aldosterone-producing adenomas. J Clin Endocrinol Metab, 2006,91:1136-42.
31. Ye P, Mariniello B, Mantero F et al. G-protein-coupled receptors in aldosterone-producing adenomas:a potential cause of hyperaldosteronism. J Endocrinol,2007,195:39-48.
32. Aguilera G. Factors controlling steroid biosynthesis in the zona glomerulosa of the adrenal. J Steroid Biochem Mol Biol,1993,45:147-51.
33. Hilbers U, Peters J, Bornstein SR et al. Local renin-angiotensin system is involved in K+-induced aldosterone secretion from human adrenocortical NCI-H295 cells. Hypertension,1999,33:1025-30.
34. Belloni AS, Andreis PG, Macchi V et al. Distribution and functional significance of angiotensin-Ⅱ AT1-and AT2-receptor subtypes in the rat adrenal gland. Endocr Res, 1998,24:1-15.
35. Nakajima M, Hutchinson HG, Fujinaga M et al. The angiotensin Ⅱ type 2 (AT2) receptor antagonizes the growth effects of the AT1 receptor:gain-of-function study using gene transfer. Proc Natl Acad Sci USA,1995,92:10663-7.
36. Wu L, Iwai M, Nakagami H et al. Effect of angiotensin Ⅱ type 1 receptor blockade on cardiac remodeling in angiotensin Ⅱ type 2 receptor null mice. Arterioscler Thromb Vasc Biol,2002,22:49-54.
37. Brede M, Roell W, Ritter O et al. Cardiac hypertrophy is associated with decreased eNOS expression in angiotensin AT2 receptor-deficient mice. Hypertension,2003, 42:1177-82.
38. Martin MM and Elton TS. The sequence and genomic organization of the human type 2 angiotensin Ⅱ receptor. Biochem Biophys Res Commun,1995,209:554-62.
39. Bonnardeaux A, Davies E, Jeunemaitre X et al. Angiotensin Ⅱ type 1 receptor gene polymorphisms in human essential hypertension. Hypertension,1994,24:63-9.
40. Kainulainen K, Perola M, Terwilliger J et al. Evidence for involvement of the type 1 angiotensin Ⅱ receptor locus in essential hypertension. Hypertension,1999,33: 844-9.
41. Diez J, Laviades C, Orbe J et al. The A1166C polymorphism of the ATI receptor gene is associated with collagen type I synthesis and myocardial stiffness in hypertensives. J Hypertens,2003,21:2085-92.
42. Zhang Y, Zhang KX, Wang GL et al. Angiotensin Ⅱ type 2 receptor gene polymorphisms and essential hypertension. Acta Pharmacol Sin,2003,24:1089-93.
43. Sauer S, Lechner D, Berlin K et al. A novel procedure for efficient genotyping of single nucleotide polymorphisms. Nucleic Acids Res,2000,28:E13.
44. Takatsu K, Yokomaku T, Kurata S et al. A new approach to SNP genotyping with fluorescently labeled mononucleotides. Nucleic Acids Res,2004,32:e60.
1. Conn JW. Presidential address. Ⅰ. Painting background. Ⅱ. Primary aldosteronism, a new clinical syndrome. J Lab Clin Med,1955,45:3-17.
2. Gordon RD, Stowasser M, Tunny TJ et al. High incidence of primary aldosteronism in 199 patients referred with hypertension. Clin Exp Pharmacol Physiol,1994,21: 315-8.
3. Plouin PF, Amar L and Chatellier G. Trends in the prevalence of primary aldosteronism, aldosterone-producing adenomas, and surgically correctable aldosterone-dependent hypertension. Nephrol Dial Transplant,2004,19:774-7.
4. Loh KC, Koay ES, Khaw MC et al. Prevalence of primary aldosteronism among Asian hypertensive patients in Singapore. J Clin Endocrinol Metab,2000,85: 2854-9.
5. Gallay BJ, Ahmad S, Xu L et al. Screening for primary aldosteronism without discontinuing hypertensive medications:plasma aldosterone-renin ratio. Am J Kidney Dis,2001,37:699-705.
6. Eide IK, Torjesen PA, Drolsum A et al. Low-renin status in therapy-resistant hypertension:a clue to efficient treatment. J Hypertens,2004,22:2217-26.
7. Strauch B, Zelinka T, Hampf M et al. Prevalence of primary hyperaldosteronism in moderate to severe hypertension in the Central Europe region. J Hum Hypertens, 2003,17:349-52.
8. Milliez P, Girerd X, Plouin PF et al. Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol, 2005,45:1243-8.
9. Stewart PM. Mineralocorticoid hypertension. Lancet,1999,353:1341-7.
10. Giacchetti G, Mulatero P, Mantero F et al. Primary aldosteronism, a major form of low renin hypertension:from screening to diagnosis. Trends Endocrinol Metab, 2008,19:104-8.
11. Plouin PF, Rossignol P and Amar L. Selection of patients for surgery for primary aldosteronism. Clin Exp Pharmacol Physiol,2008,35:522-5.
12. Meyer A, Brabant G and Behrend M. Long-term follow-up after adrenalectomy for primary aldosteronism. World J Surg,2005,29:155-9.
13. Lumachi F, Ermani M, Basso SM et al. Long-term results of adrenalectomy in patients with aldosterone-producing adenomas:multivariate analysis of factors affecting unresolved hypertension and review of the literature. Am Surg,2005,71: 864-9.
14. Harris DA, Au-Yong I, Basnyat PS et al. Review of surgical management of aldosterone secreting tumours of the adrenal cortex. Eur J Surg Oncol,2003,29: 467-74.
15. Zarnegar R, Young WF, Jr., Lee J et al. The aldosteronoma resolution score: predicting complete resolution of hypertension after adrenalectomy for aldosteronoma. Ann Surg,2008,247:511-8.
16. de Gasparo M, Catt KJ, Inagami T et al. International union of pharmacology. XXIII. The angiotensin Ⅱ receptors. Pharmacol Rev,2000,52:415-72.
17. Gard PR. The role of angiotensin Ⅱ in cognition and behaviour. Eur J Pharmacol, 2002,438:1-14.
18. McKinley MJ, Albiston AL, Allen AM et al. The brain renin-angiotensin system: location and physiological roles. Int J Biochem Cell Biol,2003,35:901-18.
19. Thomas WG and Mendelsohn FA. Angiotensin receptors:form and function and distribution. Int J Biochem Cell Biol,2003,35:774-9.
20. Widdop RE, Jones ES, Hannan RE et al. Angiotensin AT2 receptors:cardiovascular hope or hype? Br J Pharmacol,2003,140:809-24.
21. Nakajima M, Hutchinson HG, Fujinaga M et al. The angiotensin Ⅱ type 2 (AT2) receptor antagonizes the growth effects of the AT1 receptor:gain-of-function study using gene transfer. Proc Natl Acad Sci USA,1995,92:10663-7.
22. Inagami T, Eguchi S, Numaguchi K et al. Cross-talk between angiotensin Ⅱ receptors and the tyrosine kinases and phosphatases. J Am Soc Nephrol,1999,10 Suppl11:S57-61.
23. Wu L, Iwai M, Nakagami H et al. Effect of angiotensin Ⅱ type 1 receptor blockade on cardiac remodeling in angiotensin Ⅱ type 2 receptor null mice. Arterioscler Thromb Vasc Biol,2002,22:49-54.
24. Xu J, Carretero OA, Liu YH et al. Role of AT2 receptors in the cardioprotective effect of AT1 antagonists in mice. Hypertension,2002,40:244-50.
25. Brede M, Roell W, Ritter O et al. Cardiac hypertrophy is associated with decreased eNOS expression in angiotensin AT2 receptor-deficient mice. Hypertension,2003, 42:1177-82.
26. Oishi Y, Ozono R, Yano Y et al. Cardioprotective role of AT2 receptor in postinfarction left ventricular remodeling. Hypertension,2003,41:814-8.
27. Sawka AM, Young WF, Thompson GB et al. Primary aldosteronism:factors associated with normalization of blood pressure after surgery. Ann Intern Med,2001, 135:258-61.
28. Blumenfeld JD, Sealey JE, Schlussel Y et al. Diagnosis and treatment of primary hyperaldosteronism. Ann Intern Med,1994,121:877-85.
29. Pang TC, Bambach C, Monaghan JC et al. Outcomes of laparoscopic adrenalectomy for hyperaldosteronism. ANZ J Surg,2007,77:768-73.
30. Massien-Simon C, Battaglia C, Chatellier G et al. [Conn's adenoma. Diagnostic and prognostic value of the measurement of potassium, renin, aldosterone levels and the aldosterone/renin ratio]. Presse Med,1995,24:1238-42.
1. Stewart PM. Mineralocorticoid hypertension. Lancet,1999,353:1341-7.
2. Vinson GP, Ho MM and Puddefoot JR. The distribution of angiotensin Ⅱ type 1 receptors, and the tissue renin-angiotensin systems. Mol Med Today,1995,1:35-9.
3. Cook MD, Phillips MI, Cook VI et al. Angiotensin Ⅱ receptor subtypes on adrenal adenoma in primary hyperaldosteronism. J Am Soc Nephrol,1993,4:111-6.
4. Schmieder RE, Erdmann J, Delles C et al. Effect of the angiotensin Ⅱ type 2-receptor gene (+1675 G/A) on left ventricular structure in humans. J Am Coll Cardiol,2001,37:175-82.
5. Alfakih K, Maqbool A, Sivananthan M et al. Left ventricle mass index and the common, functional, X-linked angiotensin Ⅱ type-2 receptor gene polymorphism (-1332 G/A) in patients with systemic hypertension. Hypertension,2004,43: 1189-94.
6. Koh WP, Yuan JM, Van Den Berg D et al. Polymorphisms in angiotensin Ⅱ type 1 receptor and angiotensin I-converting enzyme genes and breast cancer risk among Chinese women in Singapore. Carcinogenesis,2005,26:459-64.
7. de Gasparo M, Catt KJ, Inagami T et al. International union of pharmacology. XXIII. The angiotensin Ⅱ receptors. Pharmacol Rev,2000,52:415-72.
8. Opocher G, Rocco S, Cimolato M et al. Angiotensin Ⅱ receptors in cortical and medullary adrenal tumors. J Clin Endocrinol Metab,1997,82:865-9.
9. Pawlikowski M, Winczyk K and Sledz B. Immunohistochemical detection of angiotensin receptors AT1 and AT2 in adrenal tumors. Folia Histochem Cytobiol, 2008,46:51-5.
10. Nawata H, Takayanagi R, Ohnaka K et al. Type 1 angiotensin Ⅱ receptors of adrenal tumors. Steroids,1995,60:28-34.
11. Schubert B, Fassnacht M, Beuschlein F et al. Angiotensin Ⅱ type 1 receptor and ACTH receptor expression in human adrenocortical neoplasms. Clin Endocrinol (Oxf),2001,54:627-32.
12. Tissir F, Riviere M, Guo DF et al. Localization of the genes encoding the three rat angiotensin Ⅱ receptors, Agtr1a, Agtr1b, Agtr2, and the human AGTR2 receptor respectively to rat chromosomes 17q12,2q24 and Xq34, and the human Xq22. Cytogenet Cell Genet,1995,71:77-80.
13. Martin MM and Elton TS. The sequence and genomic organization of the human type 2 angiotensin Ⅱreceptor. Biochem Biophys Res Commun,1995,209:554-62.
14. Grady EF, Sechi LA, Griffin CA et al. Expression of AT2 receptors in the developing rat fetus. J Clin Invest,1991,88:921-33.
15. Inagami T, Eguchi S, Numaguchi K et al. Cross-talk between angiotensin Ⅱ receptors and the tyrosine kinases and phosphatases. J Am Soc Nephrol,1999,10 Suppl11:S57-61.
16. Nakajima M, Hutchinson HG, Fujinaga M et al. The angiotensin Ⅱ type 2 (AT2) receptor antagonizes the growth effects of the AT1 receptor:gain-of-function study using gene transfer. Proc Natl Acad Sci USA,1995,92:10663-7.
17. Carey RM, Wang ZQ and Siragy HM. Role of the angiotensin type 2 receptor in the regulation of blood pressure and renal function. Hypertension,2000,35:155-63.
18. Huang XC, Richards EM and Sumners C. Mitogen-activated protein kinases in rat brain neuronal cultures are activated by angiotensin Ⅱ type 1 receptors and inhibited by angiotensin Ⅱ type 2 receptors. J Biol Chem,1996,271:15635-41.
19. Horiuchi M, Hayashida W, Akishita M et al. Stimulation of different subtypes of angiotensin Ⅱ receptors, AT1 and AT2 receptors, regulates STAT activation by negative crosstalk. Circ Res,1999,84:876-82.
20. Lehtonen JY, Daviet L, Nahmias C et al. Analysis of functional domains of angiotensin Ⅱ type 2 receptor involved in apoptosis. Mol Endocrinol,1999,13: 1051-60.
21. Wolf G, Harendza S, Schroeder R et al. Angiotensin Ⅱ's antiproliferative effects mediated through AT2-receptors depend on down-regulation of SM-20. Lab Invest, 2002,82:1305-17.
22. Herrmann SM, Nicaud V, Schmidt-Petersen K et al. Angiotensin Ⅱ type 2 receptor gene polymorphism and cardiovascular phenotypes:the GLAECO and GLAOLD studies. Eur J Heart Fail,2002,4:707-12.
23. Jin XQ, Fukuda N, Su JZ et al. Angiotensin Ⅱ type 2 receptor gene transfer downregulates angiotensin Ⅱ type 1a receptor in vascular smooth muscle cells. Hypertension,2002,39:1021-7.
24. Kuznetsova T, Staessen JA, Thijs L et al. Left ventricular mass in relation to genetic variation in angiotensin Ⅱ receptors, renin system genes, and sodium excretion. Circulation,2004,110:2644-50.
25. Nishimura H, Yerkes E, Hohenfellner K et al. Role of the angiotensin type 2 receptor gene in congenital anomalies of the kidney and urinary tract, CAKUT, of mice and men. Mol Cell,1999,3:1-10.
26. Warnecke C, Mugrauer P, Surder D et al. Intronic ANG Ⅱ type 2 receptor gene polymorphism 1675 G/A modulates receptor protein expression but not mRNA splicing. Am J Physiol Regul Integr Comp Physiol,2005,289:R1729-35.
1. de Gasparo M, Catt KJ, Inagami T et al. International union of pharmacology. XXIII. The angiotensin Ⅱ receptors. Pharmacol Rev,2000,52:415-72.
2. Gard PR. The role of angiotensin Ⅱ in cognition and behaviour. Eur J Pharmacol, 2002,438:1-14.
3. McKinley MJ, Albiston AL, Allen AM et al. The brain renin-angiotensin system: location and physiological roles.Int J Biochem Cell Biol,2003,35:901-18.
4. Thomas WG and Mendelsohn FA. Angiotensin receptors:form and function and distribution. Int J Biochem Cell Biol,2003,35:774-9.
5. Speth RC, Thompson SM and Johns SJ. Angiotensin Ⅱ receptors. Structural and functional considerations. Adv Exp Med Biol,1995,377:169-92.
6. de Gasparo M and Siragy HM. The AT2 receptor:fact, fancy and fantasy. Regul Pept,1999,81:11-24.
7. Eguchi S and Inagami T. Signal transduction of angiotensin Ⅱ type 1 receptor through receptor tyrosine kinase. Regul Pept,2000,91:13-20.
8. Saito Y and Berk BC. Angiotensin Ⅱ-mediated signal transduction pathways. Curr Hypertens Rep,2002,4:167-71.
9. Wu Z, Maric C, Roesch DM et al. Estrogen regulates adrenal angiotensin AT1 receptors by modulating AT1 receptor translation. Endocrinology,2003,144: 3251-61.
10. Takekoshi K, Ishii K, Shibuya S et al. Angiotensin Ⅱ type 2 receptor counter-regulates type 1 receptor in catecholamine synthesis in cultured porcine adrenal medullary chromaffin cells. Hypertension,2002,39:142-8.
11. Chow L, Rezmann L, Catt KJ et al. Role of the renin-angiotensin system in prostate cancer. Mol Cell Endocrinol,2009,302:219-29.
12. Martin MM and Elton TS. The sequence and genomic organization of the human type 2 angiotensin Ⅱ receptor. Biochem Biophys Res Commun,1995,209: 554-62.
13. Horiuchi M, Akishita M and Dzau VJ. Recent progress in angiotensin Ⅱ type 2 receptor research in the cardiovascular system. Hypertension,1999,33:613-21.
14. Curnow KM, Pascoe L, Davies E et al. Alternatively spliced human type 1 angiotensin Ⅱ receptor mRNAs are translated at different efficiencies and encode two receptor isoforms. Mol Endocrinol,1995,9:1250-62.
15. Xu K and Murphy TJ. Reconstitution of angiotensin receptor mRNA down-regulation in vascular smooth muscle. Post-transcriptional control by protein kinase a but not mitogenic signaling directed by the 5'-untranslated region. J Biol Chem,2000,275:7604-11.
16. Qian H, Pipolo L and Thomas WG Association of beta-Arrestin 1 with the type 1A angiotensin Ⅱ receptor involves phosphorylation of the receptor carboxyl terminus and correlates with receptor internalization. Mol Endocrinol,2001,15: 1706-19.
17. Sasaki K, Yamano Y, Bardhan S et al. Cloning and expression of a complementary DNA encoding a bovine adrenal angiotensin Ⅱ type-1 receptor. Nature,1991,351: 230-3.
18. Murphy TJ, Alexander RW, Griendling KK et al. Isolation of a cDNA encoding the vascular type-1 angiotensin Ⅱ receptor. Nature,1991,351:233-6.
19. Sandberg K, Ji H, Clark AJ et al. Cloning and expression of a novel angiotensin Ⅱ receptor subtype. J Biol Chem,1992,267:9455-8.
20. Sasamura H, Hein L, Krieger JE et al. Cloning, characterization, and expression of two angiotensin receptor (AT-1) isoforms from the mouse genome. Biochem Biophys Res Commun,1992,185:253-9.
21. Konishi H, Kuroda S, Inada Y et al. Novel subtype of human angiotensin Ⅱ type 1 receptor:cDNA cloning and expression. Biochem Biophys Res Commun,1994, 199:467-74.
22. Iwai N, Inagami T, Ohmichi N et al. Differential regulation of rat AT 1a and AT1b receptor mRNA. Biochem Biophys Res Commun,1992,188:298-303.
23. Gasc JM, Shanmugam S, Sibony M et al. Tissue-specific expression of type 1 angiotensin II receptor subtypes. An in situ hybridization study. Hypertension, 1994,24:531-7.
24. Audoly LP, Oliverio MI and Coffman TM. Insights into the functions of type 1 (AT1) angiotensin Ⅱ receptors provided by gene targeting. Trends Endocrinol Metab,2000,11:263-9.
25. Eguchi S, Dempsey PJ, Frank GD et al. Activation of MAPKs by angiotensin Ⅱ in vascular smooth muscle cells. Metalloprotease-dependent EGF receptor activation is required for activation of ERK and p38 MAPK but not for JNK. J Biol Chem, 2001,276:7957-62.
26. Thomas WG, Brandenburger Y, Autelitano DJ et al. Adenoviral-directed expression of the type 1A angiotensin receptor promotes cardiomyocyte hypertrophy via transactivation of the epidermal growth factor receptor. Circ Res, 2002,90:135-42.
27. Asakura M, Kitakaze M, Takashima S et al. Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF:metalloproteinase inhibitors as a new therapy. Nat Med,2002,8:35-40.
28. Gomez RA, Lynch KR, Chevalier RL et al. Renin and angiotensinogen gene expression in maturing rat kidney. Am J Physiol,1988,254:F582-7.
29. Kakuchi J, Ichiki T, Kiyama S et al. Developmental expression of renal angiotensin Ⅱ receptor genes in the mouse. Kidney Int,1995,47:140-7.
30. Kim HS, Krege JH, Kluckman KD et al. Genetic control of blood pressure and the angiotensinogen locus. Proc Natl Acad Sci USA,1995,92:2735-9.
31. Matsusaka T, Nishimura H, Utsunomiya H et al. Chimeric mice carrying'regional' targeted deletion of the angiotensin type 1A receptor gene. Evidence against the role for local angiotensin in the in vivo feedback regulation of renin synthesis in juxtaglomerular cells. J Clin Invest,1996,98:1867-77.
32. Ito M, Oliverio MI, Mannon PJ et al. Regulation of blood pressure by the type 1A angiotensin Ⅱ receptor gene. Proc Natl Acad Sci USA,1995,92:3521-5.
33. Ichiki T, Labosky PA, Shiota C et al. Effects on blood pressure and exploratory behaviour of mice lacking angiotensin Ⅱ type-2 receptor. Nature,1995,377: 748-50.
34. Hein L, Barsh GS, Pratt RE et al. Behavioural and cardiovascular effects of disrupting the angiotensin Ⅱ type-2 receptor in mice. Nature,1995,377:744-7.
35. Oliverio MI, Kim HS, Ito M et al. Reduced growth, abnormal kidney structure, and type 2 (AT2) angiotensin receptor-mediated blood pressure regulation in mice lacking both AT1A and AT1B receptors for angiotensin Ⅱ. Proc Natl Acad Sci U S A,1998,95:15496-501.
36. Chen X, Li W, Yoshida H et al. Targeting deletion of angiotensin type 1B receptor gene in the mouse. Am J Physiol,1997,272:F299-304.
37. Tsuchida S, Matsusaka T, Chen X et al. Murine double nullizygotes of the angiotensin type 1A and 1B receptor genes duplicate severe abnormal phenotypes of angiotensinogen nullizygotes. J Clin Invest,1998,101:755-60.
38. MacTaggart TE, Ito M, Smithies O et al. Mouse angiotensin receptor genes Agtrla and Agtrlb map to chromosomes 13 and 3. Mamm Genome,1997,8:294-5.
39. Krege JH, John SW, Langenbach LL et al. Male-female differences in fertility and blood pressure in ACE-deficient mice. Nature,1995,375:146-8.
40. Benetos A, Topouchian J, Ricard S et al. Influence of angiotensin Ⅱ type 1 receptor polymorphism on aortic stiffness in never-treated hypertensive patients. Hypertension,1995,26:44-7.
41. Bonnardeaux A, Davies E, Jeunemaitre X et al. Angiotensin Ⅱ type 1 receptor gene polymorphisms in human essential hypertension. Hypertension,1994,24: 63-9.
42. Oliverio MI, Best CF, Kim HS et al. Angiotensin Ⅱ responses in AT1A receptor-deficient mice:a role for AT1B receptors in blood pressure regulation. Am J Physiol,1997,272:F515-20.
43. Ichikawa I and Brenner BM. Importance of efferent arteriolar vascular tone in regulation of proximal tubule fluid reabsorption and glomerulotubular balance in the rat. J Clin Invest,1980,65:1192-201.
44. Schuster VL, Kokko JP and Jacobson HR. Angiotensin Ⅱ directly stimulates sodium transport in rabbit proximal convoluted tubules. J Clin Invest,1984,73: 507-15.
45. Kojima I, Kojima K, Kreutter D et al. The temporal integration of the aldosterone secretory response to angiotensin occurs via two intracellular pathways. J Biol Chem,1984,259:14448-57.
46. Oliverio MI, Best CF, Smithies O et al. Regulation of sodium balance and blood pressure by the AT(1A) receptor for angiotensin Ⅱ. Hypertension,2000,35:550-4.
47. Timmermans PB, Wong PC, Chiu AT et al. Angiotensin Ⅱ receptors and angiotensin Ⅱreceptor antagonists. Pharmacol Rev,1993,45:205-51.
48. Okubo S, Niimura F, Nishimura H et al. Angiotensin-independent mechanism for aldosterone synthesis during chronic extracellular fluid volume depletion. J Clin Invest,1997,99:855-60.
49. Phillips MI. Functions of angiotensin in the central nervous system. Annu Rev Physiol,1987,49:413-35.
50. Oliverio MI, Delnomdedieu M, Best CF et al. Abnormal water metabolism in mice lacking the type 1A receptor for ANGⅡ. Am J Physiol Renal Physiol,2000, 278:F75-82.
51. Bankir L and de Rouffignac C. Urinary concentrating ability:insights from comparative anatomy. Am J Physiol,1985,249:R643-66.
52. Baker KM, Booz GW and Dostal DE. Cardiac actions of angiotensinⅡ:Role of an intracardiac renin-angiotensin system. Annu Rev Physiol,1992,54:227-41.
53. Rockman HA, Wachhorst SP, Mao L et al. ANG Ⅱ receptor blockade prevents ventricular hypertrophy and ANF gene expression with pressure overload in mice. Am J Physiol,1994,266:H2468-75.
54. Kudoh S, Komuro I, Hiroi Y et al Mechanical stretch induces hypertrophic responses in cardiac myocytes of angiotensin Ⅱtype 1a receptor knockout mice. J Biol Chem,1998,273:24037-43.
55. Hamawaki M, Coffman TM, Lashus A et al. Pressure-overload hypertrophy is unabated in mice devoid of AT1A receptors. Am J Physiol,1998,274:H868-73.
56. Harada K, Komuro I, Shiojima I et al. Pressure overload induces cardiac hypertrophy in angiotensin Ⅱ type 1A receptor knockout mice. Circulation,1998, 97:1952-9.
57. Matsusaka T, Katori H, Inagami T et al. Communication between myocytes and fibroblasts in cardiac remodeling in angiotensin chimeric mice. J Clin Invest,1999, 103:1451-8.
58. Harada K, Komuro I, Hayashi D et al. Angiotensin Ⅱ type 1a receptor is involved in the occurrence of reperfusion arrhythmias. Circulation,1998,97:315-7.
59. Horiuchi M, Hayashida W, Kambe T et al. Angiotensin type 2 receptor dephosphorylates Bcl-2 by activating mitogen-activated protein kinase phosphatase-1 and induces apoptosis. J Biol Chem,1997,272:19022-6.
60. Bedecs K, Elbaz N, Sutren M et al. Angiotensin Ⅱ type 2 receptors mediate inhibition of mitogen-activated protein kinase cascade and functional activation of SHP-1 tyrosine phosphatase. Biochem J,1997,325 (Pt 2):449-54.
61. Huang XC, Richards EM and Sumners C. Mitogen-activated protein kinases in rat brain neuronal cultures are activated by angiotensin Ⅱ type 1 receptors and inhibited by angiotensin Ⅱ type 2 receptors. J Biol Chem,1996,271:15635-41.
62. Akishita M, Ito M, Lehtonen JY et al. Expression of the AT2 receptor developmentally programs extracellular signal-regulated kinase activity and influences fetal vascular growth. J Clin Invest,1999,103:63-71.
63. Fischer TA, Singh K, O'Hara DS et al. Role of AT1 and AT2 receptors in regulation of MAPKs and MKP-1 by ANG Ⅱ in adult cardiac myocytes. Am J Physiol,1998,275:H906-16.
64. Horiuchi M, Hayashida W, Akishita M et al. Stimulation of different subtypes of angiotensin Ⅱ receptors, AT1 and AT2 receptors, regulates STAT activation by negative crosstalk. Circ Res,1999,84:876-82.
65. Elbaz N, Bedecs K, Masson M et al. Functional trans-inactivation of insulin receptor kinase by growth-inhibitory angiotensin ⅡAT2 receptor. Mol Endocrinol, 2000,14:795-804.
66. Shenoy UV, Richards EM, Huang XC et al. Angiotensin Ⅱ type 2 receptor-mediated apoptosis of cultured neurons from newborn rat brain. Endocrinology,1999,140:500-9.
67. Lehtonen JY, Daviet L, Nahmias C et al. Analysis of functional domains of angiotensin Ⅱ type 2 receptor involved in apoptosis. Mol Endocrinol,1999,13: 1051-60.
68. Dimmeler S, Rippmann V, Weiland U et al. Angiotensin Ⅱ induces apoptosis of human endothelial cells. Protective effect of nitric oxide. Circ Res,1997,81: 970-6.
69. Gallinat S, Busche S, Schutze S et al. AT2 receptor stimulation induces generation of ceramides in PC12W cells. FEBS Lett,1999,443:75-9.
70. Siragy HM, Inagami T, Ichiki T et al. Sustained hypersensitivity to angiotensin Ⅱ and its mechanism in mice lacking the subtype-2 (AT2) angiotensin receptor. Proc Natl Acad Sci USA,1999,96:6506-10.
71. Siragy HM and Carey RM. The subtype 2 (AT2) angiotensin receptor mediates renal production of nitric oxide in conscious rats. J Clin Invest,1997,100:264-9.
72. Gohlke P, Pees C and Unger T. AT2 receptor stimulation increases aortic cyclic GMP in SHRSP by a kinin-dependent mechanism. Hypertension,1998,31: 349-55.
73. Jiao H, Cui XL, Torti M et al. Arachidonic acid mediates angiotensin Ⅱ effects on p21ras in renal proximal tubular cells via the tyrosine kinase-Shc-Grb2-Sos pathway. Proc Natl Acad Sci U SA,1998,95:7417-21.
74. Dulin NO, Alexander LD, Harwalkar S et al. Phospholipase A2-mediated activation of mitogen-activated protein kinase by angiotensin Ⅱ. Proc Natl Acad Sci USA,1998,95:8098-102.
75. Lokuta AJ, Cooper C, Gaa ST et al. Angiotensin Ⅱ stimulates the release of phospholipid-derived second messengers through multiple receptor subtypes in heart cells. J Biol Chem,1994,269:4832-8.
76. Buisson B, Laflamme L, Bottari SP et al. A G protein is involved in the angiotensin AT2 receptor inhibition of the T-type calcium current in non-differentiated NG108-15 cells. J Biol Chem,1995,270:1670-4.
77. Zhu M, Gelband CH, Moore JM et al. Angiotensin Ⅱ type 2 receptor stimulation of neuronal delayed-rectifier potassium current involves phospholipase A2 and arachidonic acid. J Neurosci,1998,18:679-86.
78. Laflamme L, Gasparo M, Gallo JM et al. Angiotensin Ⅱ induction of neurite outgrowth by AT2 receptors in NG108-15 cells. Effect counteracted by the AT1 receptors. J Biol Chem,1996,271:22729-35.
79. Stroth U, Meffert S, Gallinat S et al. Angiotensin Ⅱ and NGF differentially influence microtubule proteins in PC12W cells:role of the AT2 receptor. Brain Res Mol Brain Res,1998,53:187-95.
80. Gendron L, Laflamme L, Rivard N et al. Signals from the AT2 (angiotensin type 2) receptor of angiotensin Ⅱ inhibit p21ras and activate MAPK (mitogen-activated protein kinase) to induce morphological neuronal differentiation in NG108-15 cells. Mol Endocrinol,1999,13:1615-26.
81. Cote F, Laflamme L, Payet MD et al. Nitric oxide, a new second messenger involved in the action of angiotensin Ⅱ on neuronal differentiation of NG108-15 cells. Endocr Res,1998,24:403-7.
82. Christopoulos A and El-Fakahany EE. The generation of nitric oxide by G protein-coupled receptors. Life Sci,1999,64:1-15.
83. Parenti A, Morbidelli L, Cui XL et al. Nitric oxide is an upstream signal of vascular endothelial growth factor-induced extracellular signal-regulated kinasel/2 activation in postcapillary endothelium. J Biol Chem,1998,273: 4220-6.
84. Masaki H, Kurihara T, Yamaki A et al. Cardiac-specific overexpression of angiotensin Ⅱ AT2 receptor causes attenuated response to AT1 receptor-mediated pressor and chronotropic effects. J Clin Invest,1998,101:527-35.
85. Liu KL, Lo M, Grouzmann E et al. The subtype 2 of angiotensin Ⅱ receptors and pressure-natriuresis in adult rat kidneys. Br J Pharmacol,1999,126:826-32.
86. Yoshimura Y, Karube M, Aoki H et al. Angiotensin Ⅱ induces ovulation and oocyte maturation in rabbit ovaries via the AT2 receptor subtype. Endocrinology, 1996,137:1204-11.
87. Kotani E, Sugimoto M, Kamata H et al. Biological roles of angiotensin Ⅱ via its type 2 receptor during rat follicle atresia. Am J Physiol,1999,276:E25-33.
88. Okuyama S, Sakagawa T, Chaki S et al. Anxiety-like behavior in mice lacking the angiotensin Ⅱ type-2 receptor. Brain Res,1999,821:150-9.
89. Watanabe T, Hashimoto M, Okuyama S et al. Effects of targeted disruption of the mouse angiotensin II type 2 receptor gene on stress-induced hyperthermia. J Physiol,1999,515 (Pt 3):881-5.
90. Lucius R, Gallinat S, Rosenstiel P et al. The angiotensin Ⅱ type 2 (AT2) receptor promotes axonal regeneration in the optic nerve of adult rats. J Exp Med,1998, 188:661-70.
91. Levy BI, Benessiano J, Henrion D et al. Chronic blockade of AT2-subtype receptors prevents the effect of angiotensin Ⅱ on the rat vascular structure. J Clin Invest,1996,98:418-25.
92. Bartunek J, Weinberg EO, Tajima M et al. Angiotensin Ⅱ type 2 receptor blockade amplifies the early signals of cardiac growth response to angiotensin Ⅱ in hypertrophied hearts. Circulation,1999,99:22-5.
93. Ohkubo N, Matsubara H, Nozawa Y et al. Angiotensin type 2 receptors are reexpressed by cardiac fibroblasts from failing myopathic hamster hearts and inhibit cell growth and fibrillar collagen metabolism. Circulation,1997,96: 3954-62.
94. Ma J, Nishimura H, Fogo A et al. Accelerated fibrosis and collagen deposition develop in the renal interstitium of angiotensin type 2 receptor null mutant mice during ureteral obstruction. Kidney Int,1998,53:937-44.
95. Morrissey JJ and Klahr S. Effect of AT2 receptor blockade on the pathogenesis of renal fibrosis. Am J Physiol,1999,276:F39-45.
96. Nishimura H, Yerkes E, Hohenfellner K et al. Role of the angiotensin type 2 receptor gene in congenital anomalies of the kidney and urinary tract, CAKUT, of mice and men. Mol Cell,1999,3:1-10.
97. Miura S and Karnik SS. Ligand-independent signals from angiotensin Ⅱ type 2 receptor induce apoptosis. Embo J,2000,19:4026-35.
98. Jin XQ, Fukuda N, Su JZ et al. Angiotensin Ⅱ type 2 receptor gene transfer downregulates angiotensin Ⅱ type 1a receptor in vascular smooth muscle cells. Hypertension,2002,39:1021-7.
99. Su JZ, Fukuda N, Jin XQ et al. Effect of AT2 receptor on expression of AT1 and TGF-beta receptors in VSMCs from SHR. Hypertension,2002,40:853-8.
100. D'Amore A, Black MJ and Thomas WG The angiotensin Ⅱtype 2 receptor causes constitutive growth of cardiomyocytes and does not antagonize angiotensin Ⅱ type 1 receptor-mediated hypertrophy. Hypertension,2005,46:1347-54.
101. Falcon BL, Veerasingham SJ, Sumners C et al. Angiotensin Ⅱ type 2 receptor-mediated gene expression profiling in human coronary artery endothelial cells. Hypertension,2005,45:692-7.
102. Unger T, Chung O, Csikos T et al. Angiotensin receptors. J Hypertens Suppl,1996, 14:S95-103.
103. Simon G, Illyes G and Csiky B. Structural vascular changes in hypertension:role of angiotensin Ⅱ, dietary sodium supplementation, blood pressure, and time. Hypertension,1998,32:654-60.
104. Weber KT. Extracellular matrix remodeling in heart failure:a role for de novo angiotensin Ⅱ generation. Circulation,1997,96:4065-82.
105. Widdop RE, Jones ES, Hannan RE et al. Angiotensin AT2 receptors: cardiovascular hope or hype? Br J Pharmacol,2003,140:809-24.
106. Scheuer DA and Perrone MH. Angiotensin type 2 receptors mediate depressor phase of biphasic pressure response to angiotensin. Am J Physiol,1993,264: R917-23.
107. Munzenmaier DH and Greene AS. Opposing actions of angiotensin Ⅱ on microvascular growth and arterial blood pressure. Hypertension,1996,27:760-5.
108. Li XC and Widdop RE. AT2 receptor-mediated vasodilatation is unmasked by AT1 receptor blockade in conscious SHR. Br J Pharmacol,2004,142:821-30.
109. Li H, Gao Y, Grobe JL et al. Potentiation of the antihypertensive action of losartan by peripheral overexpression of the ANG Ⅱ type 2 receptor. Am J Physiol Heart Circ Physiol,2007,292:H727-35.
110. Hiyoshi H, Yayama K, Takano M et al. Stimulation of cyclic GMP production via AT2 and B2 receptors in the pressure-overloaded aorta after banding. Hypertension,2004,43:1258-63.
111. Yayama K, Horii M, Hiyoshi H et al. Up-regulation of angiotensin Ⅱ type 2 receptor in rat thoracic aorta by pressure-overload. J Pharmacol Exp Ther,2004, 308:736-43.
112. Yayama K, Hiyoshi H, Imazu D et al. Angiotensin Ⅱ stimulates endothelial NO synthase phosphorylation in thoracic aorta of mice with abdominal aortic banding via type 2 receptor. Hypertension,2006,48:958-64.
113. Savoia C, Ebrahimian T, He Y et al. Angiotensin Ⅱ/AT2 receptor-induced vasodilation in stroke-prone spontaneously hypertensive rats involves nitric oxide and cGMP-dependent protein kinase. J Hypertens,2006,24:2417-22.
114. Hiyoshi H, Yayama K, Takano M et al. Angiotensin type 2 receptor-mediated phosphorylation of eNOS in the aortas of mice with 2-kidney,1-clip hypertension. Hypertension,2005,45:967-73.
115. Savoia C, Tabet F, Yao G et al. Negative regulation of RhoA/Rho kinase by angiotensin Ⅱ type 2 receptor in vascular smooth muscle cells:role in angiotensin Ⅱ-induced vasodilation in stroke-prone spontaneously hypertensive rats. J Hypertens,2005,23:1037-45.
116. Savoia C, Touyz RM, Volpe M et al. Angiotensin type 2 receptor in resistance arteries of type 2 diabetic hypertensive patients. Hypertension,2007,49:341-6.
117. You D, Loufrani L, Baron C et al. High blood pressure reduction reverses angiotensin Ⅱ type 2 receptor-mediated vasoconstriction into vasodilation in spontaneously hypertensive rats. Circulation,2005,111:1006-11.
118. Booz GW. Cardiac angiotensin AT2 receptor:what exactly does it do? Hypertension,2004,43:1162-3.
119. Regitz-Zagrosek V, Friedel N, Heymann A et al. Regulation, chamber localization, and subtype distribution of angiotensin Ⅱ receptors in human hearts. Circulation, 1995,91:1461-71.
120. Asano K, Dutcher DL, Port JD et al. Selective downregulation of the angiotensin Ⅱ AT1-receptor subtype in failing human ventricular myocardium. Circulation, 1997,95:1193-200.
121. Haywood GA, Gullestad L, Katsuya T et al. AT1 and AT2 angiotensin receptor gene expression in human heart failure. Circulation,1997,95:1201-6.
122. Tsutsumi Y, Matsubara H, Ohkubo N et al. Angiotensin Ⅱ type 2 receptor is upregulated in human heart with interstitial fibrosis, and cardiac fibroblasts are the major cell type for its expression. Circ Res,1998,83:1035-46.
123. Wharton J, Morgan K, Rutherford RA et al. Differential distribution of angiotensin AT2 receptors in the normal and failing human heart. J Pharmacol Exp Ther,1998,284:323-36.
124. Brede M, Roell W, Ritter O et al. Cardiac hypertrophy is associated with decreased eNOS expression in angiotensin AT2 receptor-deficient mice. Hypertension,2003,42:1177-82.
125. Oishi Y, Ozono R, Yano Y et al. Cardioprotective role of AT2 receptor in postinfarction left ventricular remodeling. Hypertension,2003,41:814-8.
126. Xu J, Carretero OA, Liu YH et al. Role of AT2 receptors in the cardioprotective effect of AT1 antagonists in mice. Hypertension,2002,40:244-50.
127. Yan X, Price RL, Nakayama M et al. Ventricular-specific expression of angiotensin Ⅱ type 2 receptors causes dilated cardiomyopathy and heart failure in transgenic mice. Am J Physiol Heart Circ Physiol,2003,285:H2179-87.
128. Senbonmatsu T, Ichihara S, Price E, Jr. et al. Evidence for angiotensinⅡtype 2 receptor-mediated cardiac myocyte enlargement during in vivo pressure overload. J Clin Invest,2000,106:R1-5.
129. Ichihara S, Senbonmatsu T, Price E, Jr. et al. Angiotensin Ⅱ type 2 receptor is essential for left ventricular hypertrophy and cardiac fibrosis in chronic angiotensin Ⅱ-induced hypertension. Circulation,2001,104:346-51.
130. Ichihara S, Senbonmatsu T, Price E, Jr. et al. Targeted deletion of angiotensin Ⅱ type 2 receptor caused cardiac rupture after acute myocardial infarction. Circulation,2002,106:2244-9.
131. Lako-Futo Z, Szokodi I, Sarman B et al. Evidence for a functional role of angiotensin Ⅱ type 2 receptor in the cardiac hypertrophic process in vivo in the rat heart. Circulation,2003,108:2414-22.
132. Yang Z, Bove CM, French BA et al. Angiotensin Ⅱtype 2 receptor overexpression preserves left ventricular function after myocardial infarction. Circulation,2002, 106:106-11.
133. Bove CM, Gilson WD, Scott CD et al. The angiotensin Ⅱ type 2 receptor and improved adjacent region function post-MI. J Cardiovasc Magn Reson,2005,7: 459-64.
134. Bove CM, Yang Z, Gilson WD et al. Nitric oxide mediates benefits of angiotensin Ⅱ type 2 receptor overexpression during post-infarct remodeling. Hypertension, 2004,43:680-5.
135. Liu YH, Yang XP, Sharov VG et al. Effects of angiotensin-converting enzyme inhibitors and angiotensin Ⅱ type 1 receptor antagonists in rats with heart failure. Role of kinins and angiotensin Ⅱ type 2 receptors. J Clin Invest,1997,99: 1926-35.
136. Isbell DC, Voros S, Yang Z et al. Interaction between bradykinin subtype 2 and angiotensin Ⅱ type 2 receptors during post-MI left ventricular remodeling. Am J Physiol Heart Circ Physiol,2007,293:H3372-8.
137. Wu L, Iwai M, Nakagami H et al. Effect of angiotensin Ⅱ type 1 receptor blockade on cardiac remodeling in angiotensin Ⅱ type 2 receptor null mice. Arterioscler Thromb Vasc Biol,2002,22:49-54.
138. Brilla CG, Zhou G, Matsubara L et al. Collagen metabolism in cultured adult rat cardiac fibroblasts:response to angiotensin Ⅱ and aldosterone. J Mol Cell Cardiol, 1994,26:809-20.
139. Brilla CG, Zhou G, Rupp H et al. Role of angiotensin Ⅱ and prostaglandin E2 in regulating cardiac fibroblast collagen turnover. Am J Cardiol,1995,76:8D-13D.
140. Brassard P, Amiri F and Schiffrin EL. Combined angiotensin Ⅱ type 1 and type 2 receptor blockade on vascular remodeling and matrix metalloproteinases in resistance arteries. Hypertension,2005,46:598-606.
141. Lijnen PJ, Petrov VV and Fagard RH. Induction of cardiac fibrosis by angiotensin II. Methods Find Exp Clin Pharmacol,2000,22:709-23.
142. Touyz RM, He Q El Mabrouk M et al. p38 Map kinase regulates vascular smooth muscle cell collagen synthesis by angiotensin Ⅱ in SHR but not in WKY. Hypertension,2001,37:574-80.
143. Warnecke C, Kaup D, Marienfeld U et al. Adenovirus-mediated overexpression and stimulation of the human angiotensin II type 2 receptor in porcine cardiac fibroblasts does not modulate proliferation, collagen I mRNA expression and ERK1/ERK2 activity, but inhibits protein tyrosine phosphatases. J Mol Med,2001, 79:510-21.
144. Ito T, Yamakawa H, Bregonzio C et al. Protection against ischemia and improvement of cerebral blood flow in genetically hypertensive rats by chronic pretreatment with an angiotensin Ⅱ AT1 antagonist. Stroke,2002,33:2297-303.
145. Walther T, Olah L, Harms C et al. Ischemic injury in experimental stroke depends on angiotensin Ⅱ. Faseb J,2002,16:169-76.
146. Nishimura Y, Ito T and Saavedra JM. Angiotensin Ⅱ AT(1) blockade normalizes cerebrovascular autoregulation and reduces cerebral ischemia in spontaneously hypertensive rats. Stroke,2000,31:2478-86.
147. Saavedra JM, Benicky J and Zhou J. Mechanisms of the Anti-Ischemic Effect of Angiotensin Ⅱ AT(1) Receptor Antagonists in the Brain. Cell Mol Neurobiol, 2006,26:1099-111.
148. Zhu YZ, Chimon GN, Zhu YC et al. Expression of angiotensin Ⅱ AT2 receptor in the acute phase of stroke in rats. Neuroreport,2000,11:1191-4.
149. Li J, Culman J, Hortnagl H et al. Angiotensin AT2 receptor protects against cerebral ischemia-induced neuronal injury. Faseb J,2005,19:617-9.
150. Lu Q, Zhu YZ and Wong PT. Neuroprotective effects of candesartan against cerebral ischemia in spontaneously hypertensive rats. Neuroreport,2005,16: 1963-7.
151. Mogi M, Li JM, Iwanami J et al. Angiotensin Ⅱ type-2 receptor stimulation prevents neural damage by transcriptional activation of methyl methanesulfonate sensitive 2. Hypertension,2006,48:141-8.
152. Iwai M, Liu HW, Chen R et al. Possible inhibition of focal cerebral ischemia by angiotensin Ⅱ type 2 receptor stimulation. Circulation,2004,110:843-8.
153. Grammatopoulos T, Morris K, Ferguson P et al. Angiotensin protects cortical neurons from hypoxic-induced apoptosis via the angiotensin type 2 receptor. Brain Res Mol Brain Res,2002,99:114-24.
154. Reinecke K, Lucius R, Reinecke A et al. Angiotensin Ⅱ accelerates functional recovery in the rat sciatic nerve in vivo:role of the AT2 receptor and the transcription factor NF-kappaB. Faseb J,2003,17:2094-6.
155. Hein L, Meinel L, Pratt RE et al. Intracellular trafficking of angiotensin Ⅱ and its AT1 and AT2 receptors:evidence for selective sorting of receptor and ligand. Mol Endocrinol,1997,11:1266-77.
156. Doria A, Onuma T, Warram JH et al. Synergistic effect of angiotensin Ⅱ type 1 receptor genotype and poor glycaemic control on risk of nephropathy in IDDM. Diabetologia,1997,40:1293-9.
157. Chaves FJ, Pascual JM, Rovira E et al. Angiotensin Ⅱ AT1 receptor gene polymorphism and microalbuminuria in essential hypertension. Am J Hypertens, 2001,14:364-70.
158. Erdmann J, Riedel K, Rohde K et al. Characterization of polymorphisms in the promoter of the human angiotensin Ⅱ subtype 1 (AT1) receptor gene. Ann Hum Genet,1999,63:369-74.
159. Poirier O, Georges JL, Ricard S et al. New polymorphisms of the angiotensin Ⅱ type 1 receptor gene and their associations with myocardial infarction and blood pressure:the ECTIM study. Etude Cas-Temoin de l'Infarctus du Myocarde. J Hypertens,1998,16:1443-7.
160. Takahashi N, Murakami H, Kodama K et al. Association of a polymorphism at the 5'-region of the angiotensin Ⅱ type 1 receptor with hypertension. Ann Hum Genet, 2000,64:197-205.
161. Zhu X, Chang YP, Yan D et al. Associations between hypertension and genes in the renin-angiotensin system. Hypertension,2003,41:1027-34.
162. Lajemi M, Labat C, Gautier S et al. Angiotensin Ⅱ type 1 receptor-153 A/G and 1166A/C gene polymorphisms and increase in aortic stiffness with age in hypertensive subjects. J Hypertens,2001,19:407-13.
163. Kainulainen K, Perola M, Terwilliger J et al. Evidence for involvement of the type 1 angiotensin Ⅱ receptor locus in essential hypertension. Hypertension,1999,33: 844-9.
164. Wang WY, Zee RY and Morris BJ. Association of angiotensin II type 1 receptor gene polymorphism with essential hypertension. Clin Genet,1997,51:31-4.
165. Kobashi G, Hata A, Ohta K et al. A1166C variant of angiotensin Ⅱ type 1 receptor gene is associated with severe hypertension in pregnancy independently of T235 variant of angiotensinogen gene. J Hum Genet,2004,49:182-6.
166. Wang JG and Staessen JA. Genetic polymorphisms in the renin-angiotensin system:relevance for susceptibility to cardiovascular disease. Eur J Pharmacol, 2000,410:289-302.
167. Henskens LH, Spiering W, Stoffers HE et al. Effects of ACE I/D and AT1R-A1166C polymorphisms on blood pressure in a healthy normotensive primary care population:first results of the Hippocates study. J Hypertens,2003, 21:81-6.
168. Jiang Z, Zhao W, Yu F et al. Association of angiotensin Ⅱ type 1 receptor gene polymorphism with essential hypertension. Chin Med J (Engl),2001,114: 1249-51.
169. Ono K, Mannami T, Baba S et al. Lack of association between angiotensin Ⅱ type 1 receptor gene polymorphism and hypertension in Japanese. Hypertens Res,2003, 26:131-4.
170. Iliadou A, Lichtenstein P, Morgenstern R et al. Repeated blood pressure measurements in a sample of Swedish twins:heritabilities and associations with polymorphisms in the renin-angiotensin-aldosterone system. J Hypertens,2002, 20:1543-50.
171. Schmidt S, Beige J, Walla-Friedel M et al. A polymorphism in the gene for the angiotensin Ⅱtype 1 receptor is not associated with hypertension. J Hypertens, 1997,15:1385-8.
172. Tiret L, Blanc H, Ruidavets JB et al. Gene polymorphisms of the renin-angiotensin system in relation to hypertension and parental history of myocardial infarction and stroke:the PEGASE study. Projet d'Etude des Genes de 1'Hypertension Arterielle Severe a moderee Essentielle. J Hypertens,1998,16: 37-44.
173. Sierra C, Coca A, Gomez-Angelats E et al. Renin-angiotensin system genetic polymorphisms and cerebral white matter lesions in essential hypertension. Hypertension,2002,39:343-7.
174. Buraczynska M, Ksiazek P, Zaluska W et al. Angiotensin Ⅱ type 1 receptor gene polymorphism in end-stage renal disease. Nephron,2002,92:51-5.
175. Coll E, Campos B, Gonzalez-Nunez D et al. Association between the A1166C polymorphism of the angiotensin Ⅱ receptor type 1 and progression of chronic renal insufficiency. J Nephrol,2003,16:357-64.
176. Benetos A, Cambien F, Gautier S et al. Influence of the angiotensin Ⅱ type 1 receptor gene polymorphism on the effects of perindopril and nitrendipine on arterial stiffness in hypertensive individuals. Hypertension,1996,28:1081-4.
177. Benetos A, Gautier S, Ricard S et al. Influence of angiotensin-converting enzyme and angiotensin Ⅱ type 1 receptor gene polymorphisms on aortic stiffness in normotensive and hypertensive patients. Circulation,1996,94:698-703.
178. Girerd X, Hanon O, Mourad JJ et al. Lack of association between renin-angiotensin system, gene polymorphisms, and wall thickness of the radial and carotid arteries. Hypertension,1998,32:579-83.
179. Diez J, Laviades C, Orbe J et al. The A1166C polymorphism of the AT1 receptor gene is associated with collagen type Ⅰ synthesis and myocardial stiffness in hypertensives. J Hypertens,2003,21:2085-92.
180. Andersson B, Blange I and Sylven C. Angiotensin-Ⅱ type 1 receptor gene polymorphism and long-term survival in patients with idiopathic congestive heart failure. Eur J Heart Fail,1999,1:363-9.
181. Jin W, Liu Y, Sheng HH et al. Single nucleotide polymorphisms in promoter of angiotensin Ⅱ type 1 receptor gene associated with essential hypertension and coronary heart disease in Chinese population. Acta Pharmacol Sin,2003,24: 1083-8.
182. Koh WP, Yuan JM, Van Den Berg D et al. Polymorphisms in angiotensin Ⅱ type 1 receptor and angiotensin I-converting enzyme genes and breast cancer risk among Chinese women in Singapore. Carcinogenesis,2005,26:459-64.
183. Deinum J, van Gool JM, Kofflard MJ et al. Angiotensin Ⅱ type 2 receptors and cardiac hypertrophy in women with hypertrophic cardiomyopathy. Hypertension, 2001,38:1278-81.
184. Delles C, Erdmann J, Jacobi J et al. Lack of association between polymorphisms of angiotensin Ⅱ receptor genes and response to short-term angiotensin Ⅱ infusion. J Hypertens,2000,18:1573-8.
185. Zhang Y, Zhang KX, Wang GL et al. Angiotensin Ⅱ type 2 receptor gene polymorphisms and essential hypertension. Acta Pharmacol Sin,2003,24: 1089-93.
186. Alfakih K, Maqbool A, Sivananthan M et al. Left ventricle mass index and the common, functional, X-linked angiotensin Ⅱ type-2 receptor gene polymorphism (-1332 G/A) in patients with systemic hypertension. Hypertension,2004,43: 1189-94.
187. Schmieder RE, Erdmann J, Delles C et al. Effect of the angiotensin Ⅱ type 2-receptor gene (+1675 G/A) on left ventricular structure in humans. J Am Coll Cardiol,2001,37:175-82.
188. Alfakih K, Lawrance RA, Maqbool A et al. The clinical significance of a common, functional, X-linked angiotensin Ⅱ type 2-receptor gene polymorphism (-1332 G/A) in a cohort of 509 families with premature coronary artery disease. Eur Heart J,2005,26:584-9.
189. Warnecke C, Mugrauer P, Surder D et al. Intronic ANG Ⅱ type 2 receptor gene polymorphism 1675 G/A modulates receptor protein expression but not mRNA splicing. Am J Physiol Regul Integr Comp Physiol,2005,289:R1729-35.
190. Strauss MH and Hall AS. Angiotensin receptor blockers may increase risk of myocardial infarction:unraveling the ARB-MI paradox. Circulation,2006,114: 838-54.
2. Kaplan NM. Hypokalemia in the hypertensive patient, with observations on the incidence of primary aldosteronism. Ann Intern Med,1967,66:1079-90.
3. Lund JO, Nielsen MD and Giese J. Prevalence of primary aldosteronism. Acta Med Scand Suppl,1981,646:54-7.
4. Sinclair AM, Isles CG, Brown I et al. Secondary hypertension in a blood pressure clinic. Arch Intern Med,1987,147:1289-93.
5. Conn JW, Cohen EL, Rovner DR et al. Normokalemic Primary Aldosteronism. a Detectable Cause of Curable "Essential" Hypertension. Jama,1965,193:200-6.
6. Mosso L, Carvajal C, Gonzalez A et al. Primary aldosteronism and hypertensive disease. Hypertension,2003,42:161-5.
7. Schwartz GL and Turner ST. Screening for primary aldosteronism in essential hypertension:diagnostic accuracy of the ratio of plasma aldosterone concentration to plasma renin activity. Clin Chem,2005,51:386-94.
8. Gordon RD, Stowasser M, Tunny TJ et al. High incidence of primary aldosteronism in 199 patients referred with hypertension. Clin Exp Pharmacol Physiol,1994,21: 315-8.
9. Plouin PF, Amar L and Chatellier G. Trends in the prevalence of primary aldosteronism, aldosterone-producing adenomas, and surgically correctable aldosterone-dependent hypertension. Nephrol Dial Transplant,2004,19:774-7.
10. Loh KC, Koay ES, Khaw MC et al. Prevalence of primary aldosteronism among Asian hypertensive patients in Singapore. J Clin Endocrinol Metab,2000,85:2854-9.
11. Gallay BJ, Ahmad S, Xu L et al. Screening for primary aldosteronism without discontinuing hypertensive medications:plasma aldosterone-renin ratio. Am J Kidney Dis,2001,37:699-705.
12. Eide IK, Torjesen PA, Drolsum A et al. Low-renin status in therapy-resistant hypertension:a clue to efficient treatment. J Hypertens,2004,22:2217-26.
13. Strauch B, Zelinka T, Hampf M et al. Prevalence of primary hyperaldosteronism in moderate to severe hypertension in the Central Europe region. J Hum Hypertens, 2003,17:349-52.
14. Milliez P, Girerd X, Plouin PF et al. Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol,2005,45:1243-8.
15. Stewart PM. Mineralocorticoid hypertension. Lancet,1999,353:1341-7.
16. Giacchetti G, Mulatero P, Mantero F et al. Primary aldosteronism, a major form of low renin hypertension:from screening to diagnosis. Trends Endocrinol Metab,2008, 19:104-8.
17. Plouin PF, Rossignol P and Amar L. Selection of patients for surgery for primary aldosteronism. Clin Exp Pharmacol Physiol,2008,35:522-5.
18. Meyer A, Brabant G and Behrend M. Long-term follow-up after adrenalectomy for primary aldosteronism. World J Surg,2005,29:155-9.
19. Lumachi F, Ermani M, Basso SM et al. Long-term results of adrenalectomy in patients with aldosterone-producing adenomas:multivariate analysis of factors affecting unresolved hypertension and review of the literature. Am Surg,2005,71: 864-9.
20. Harris DA, Au-Yong I, Basnyat PS et al. Review of surgical management of aldosterone secreting tumours of the adrenal cortex. Eur J Surg Oncol,2003,29: 467-74.
21. Fallo F, Pistorello M, Pedini F et al. In vitro evidence for local generation of renin and angiotensin Ⅱ/Ⅲ immunoreactivity by the human adrenal gland. Acta Endocrinol (Copenh),1991,125:319-30.
22. de Gasparo M, Catt KJ, Inagami T et al. International union of pharmacology. XXIII. The angiotensin Ⅱ receptors. Pharmacol Rev,2000,52:415-72.
23. Gard PR. The role of angiotensin Ⅱ in cognition and behaviour. Eur J Pharmacol, 2002,438:1-14.
24. McKinley MJ, Albiston AL, Allen AM et al. The brain renin-angiotensin system: location and physiological roles. Int J Biochem Cell Biol,2003,35:901-18.
25. Thomas WG and Mendelsohn FA. Angiotensin receptors:form and function and distribution. Int J Biochem Cell Biol,2003,35:774-9.
26. Vinson GP, Ho MM and Puddefoot JR. The distribution of angiotensin II type 1 receptors, and the tissue renin-angiotensin systems. Mol Med Today,1995,1:35-9.
27. Aguilera G Factors controlling steroid biosynthesis in the zona glomerulosa of the adrenal. J Steroid Biochem Mol Biol,1993,45:147-51.
28. Hilbers U, Peters J, Bornstein SR et al. Local renin-angiotensin system is involved in K+-induced aldosterone secretion from human adrenocortical NCI-H295 cells. Hypertension,1999,33:1025-30.
29. Belloni AS, Andreis PG, Macchi V et al. Distribution and functional significance of angiotensin-Ⅱ AT1-and AT2-receptor subtypes in the rat adrenal gland. Endocr Res, 1998,24:1-15.
30. Nakajima M, Hutchinson HQ Fujinaga M et al. The angiotensin Ⅱ type 2 (AT2) receptor antagonizes the growth effects of the AT1 receptor:gain-of-function study using gene transfer. Proc Natl Acad Sci USA,1995,92:10663-7.
31. Inagami T, Eguchi S, Numaguchi K et al. Cross-talk between angiotensin Ⅱ receptors and the tyrosine kinases and phosphatases. J Am Soc Nephrol,1999,10 Suppl 11: S57-61.
32. Widdop RE, Jones ES, Hannan RE et al. Angiotensin AT2 receptors:cardiovascular hope or hype? Br J Pharmacol,2003,140:809-24.
33. Wu L, Iwai M, Nakagami H et al. Effect of angiotensin Ⅱ type 1 receptor blockade on cardiac remodeling in angiotensin Ⅱtype 2 receptor null mice. Arterioscler Thromb Vasc Biol,2002,22:49-54.
34. Xu J, Carretero OA, Liu YH et al. Role of AT2 receptors in the cardioprotective effect of AT1 antagonists in mice. Hypertension,2002,40:244-50.
35. Brede M, Roell W, Ritter O et al. Cardiac hypertrophy is associated with decreased eNOS expression in angiotensin AT2 receptor-deficient mice. Hypertension,2003,42: 1177-82.
36. Oishi Y, Ozono R, Yano Y et al. Cardioprotective role of AT2 receptor in postinfarction left ventricular remodeling. Hypertension,2003,41:814-8.
37. Bonnardeaux A, Davies E, Jeunemaitre X et al. Angiotensin Ⅱ type 1 receptor gene polymorphisms in human essential hypertension. Hypertension,1994,24:63-9.
38. Kainulainen K, Perola M, Terwilliger J et al. Evidence for involvement of the type 1 angiotensin Ⅱ receptor locus in essential hypertension. Hypertension,1999,33:844-9.
39. Diez J, Laviades C, Orbe J et al. The A1166C polymorphism of the AT1 receptor gene is associated with collagen type Ⅰ synthesis and myocardial stiffness in hypertensives. J Hypertens,2003,21:2085-92.
40. Koh WP, Yuan JM, Van Den Berg D et al. Polymorphisms in angiotensin Ⅱ type 1 receptor and angiotensin I-converting enzyme genes and breast cancer risk among Chinese women in Singapore. Carcinogenesis,2005,26:459-64.
41. Zhang Y, Zhang KX, Wang GL et al. Angiotensin Ⅱ type 2 receptor gene polymorphisms and essential hypertension. Acta Pharmacol Sin,2003,24:1089-93.
42. Alfakih K, Maqbool A, Sivananthan M et al. Left ventricle mass index and the common, functional, X-linked angiotensin Ⅱ type-2 receptor gene polymorphism (-1332 G/A) in patients with systemic hypertension. Hypertension,2004,43:1189-94.
43. Schmieder RE, Erdmann J, Delles C et al. Effect of the angiotensin Ⅱ type 2-receptor gene (+1675 G/A) on left ventricular structure in humans. J Am Coll Cardiol,2001, 37:175-82.
1. Milliez P, Girerd X, Plouin PF et al. Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol, 2005,45:1243-8.
2. Stewart PM. Mineralocorticoid hypertension. Lancet,1999,353:1341-7.
3. Enberg U, Volpe C, Hoog A et al. Postoperative differentiation between unilateral adrenal adenoma and bilateral adrenal hyperplasia in primary aldosteronism by mRNA expression of the gene CYP11B2. Eur J Endocrinol,2004,151:73-85.
4. Zwermann O, Beuschlein F, Lalli E et al. Clinical and molecular evidence for DAX-1 inhibition of steroidogenic factor-1-dependent ACTH receptor gene expression. Eur J Endocrinol,2005,152:769-76.
5. de Fraipont F, El Atifi M, Cherradi N et al. Gene expression profiling of human adrenocortical tumors using complementary deoxyribonucleic Acid microarrays identifies several candidate genes as markers of malignancy. J Clin Endocrinol Metab,2005,90:1819-29.
6. Reincke M, Beuschlein F, Slawik M et al. Molecular adrenocortical tumourigenesis. Eur J Clin Invest,2000,30 Suppl 3:63-8.
7. Sidhu S, Gicquel C, Bambach CP et al. Clinical and molecular aspects of adrenocortical tumourigenesis. ANZ J Surg,2003,73:727-38.
8. Fallo F, Pistorello M, Pedini F et al. In vitro evidence for local generation of renin and angiotensin Ⅱ/Ⅲ immunoreactivity by the human adrenal gland. Acta Endocrinol (Copenh),1991,125:319-30.
9. de Gasparo M, Catt KJ, Inagami T et al. International union of pharmacology. ⅩⅩⅢ. The angiotensin Ⅱ receptors. Pharmacol Rev,2000,52:415-72.
10. Gard PR. The role of angiotensin Ⅱ in cognition and behaviour. Eur J Pharmacol, 2002,438:1-14.
11. McKinley MJ, Albiston AL, Allen AM et al. The brain renin-angiotensin system: location and physiological roles. Int J Biochem Cell Biol,2003,35:901-18.
12. Thomas WG and Mendelsohn FA. Angiotensin receptors:form and function and distribution. Int J Biochem Cell Biol,2003,35:774-9.
13. Vinson GP, Ho MM and Puddefoot JR. The distribution of angiotensin Ⅱ type 1 receptors, and the tissue renin-angiotensin systems. Mol Med Today,1995,1:35-9.
14. Inagami T, Eguchi S, Numaguchi K et al. Cross-talk between angiotensin Ⅱ receptors and the tyrosine kinases and phosphatases. J Am Soc Nephrol,1999,10 Suppl11:S57-61.
15. Widdop RE, Jones ES, Hannan RE et al. Angiotensin AT2 receptors:cardiovascular hope or hype? Br J Pharmacol,2003,140:809-24.
16. Xu J, Carretero OA, Liu YH et al. Role of AT2 receptors in the cardioprotective effect of AT1 antagonists in mice. Hypertension,2002,40:244-50.
17. Oishi Y, Ozono R, Yano Y et al. Cardioprotective role of AT2 receptor in postinfarction left ventricular remodeling. Hypertension,2003,41:814-8.
18. Schmieder RE, Erdmann J, Delles C et al. Effect of the angiotensin Ⅱ type 2-receptor gene (+1675 G/A) on left ventricular structure in humans. J Am Coll Cardiol,2001,37:175-82.
19. Alfakih K, Maqbool A, Sivananthan M et al. Left ventricle mass index and the common, functional, X-linked angiotensin Ⅱ type-2 receptor gene polymorphism (-1332 G/A) in patients with systemic hypertension. Hypertension,2004,43: 1189-94.
20. Koh WP, Yuan JM, Van Den Berg D et al. Polymorphisms in angiotensin Ⅱ type 1 receptor and angiotensin I-converting enzyme genes and breast cancer risk among Chinese women in Singapore. Carcinogenesis,2005,26:459-64.
21. Bielinska M, Parviainen H, Kiiveri S et al. Origin and Molecular Pathology of Adrenocortical Neoplasms. Vet Pathol,2009.
22. Gicquel C, Bertagna X and Le Bouc Y. Recent advances in the pathogenesis of adrenocortical tumours. Eur J Endocrinol,1995,133:133-44.
23. Reincke M. Mutations in adrenocortical tumors. Horm Metab Res,1998,30: 447-55.
24. Bertherat J, Groussin L, Sandrini F et al. Molecular and functional analysis of PRKAR1A and its locus (17q22-24) in sporadic adrenocortical tumors:17q losses, somatic mutations, and protein kinase A expression and activity. Cancer Res,2003, 63:5308-19.
25. Tissier F, Cavard C, Groussin L et al. Mutations of beta-catenin in adrenocortical tumors:activation of the Wnt signaling pathway is a frequent event in both benign and malignant adrenocortical tumors. Cancer Res,2005,65:7622-7.
26. Stratakis CA. Genetics of adrenocortical tumors:gatekeepers, landscapers and conductors in symphony. Trends Endocrinol Metab,2003,14:404-10.
27. Honda T, Nakamura T, Saito Y et al. Combined primary aldosteronism and preclinical Cushing's syndrome:an unusual case presentation of adrenal adenoma. Hypertens Res,2001,24:723-6.
28. Lenzini L, Seccia TM, Aldighieri E et al. Heterogeneity of aldosterone-producing adenomas revealed by a whole transcriptome analysis. Hypertension,2007,50: 1106-13.
29. Assie G, Auzan C, Gasc JM et al. Steroidogenesis in aldosterone-producing adenoma revisited by transcriptome analysis. J Clin Endocrinol Metab,2005,90: 6638-49.
30. Saner-Amigh K, Mayhew BA, Mantero F et al. Elevated expression of luteinizing hormone receptor in aldosterone-producing adenomas. J Clin Endocrinol Metab, 2006,91:1136-42.
31. Ye P, Mariniello B, Mantero F et al. G-protein-coupled receptors in aldosterone-producing adenomas:a potential cause of hyperaldosteronism. J Endocrinol,2007,195:39-48.
32. Aguilera G. Factors controlling steroid biosynthesis in the zona glomerulosa of the adrenal. J Steroid Biochem Mol Biol,1993,45:147-51.
33. Hilbers U, Peters J, Bornstein SR et al. Local renin-angiotensin system is involved in K+-induced aldosterone secretion from human adrenocortical NCI-H295 cells. Hypertension,1999,33:1025-30.
34. Belloni AS, Andreis PG, Macchi V et al. Distribution and functional significance of angiotensin-Ⅱ AT1-and AT2-receptor subtypes in the rat adrenal gland. Endocr Res, 1998,24:1-15.
35. Nakajima M, Hutchinson HG, Fujinaga M et al. The angiotensin Ⅱ type 2 (AT2) receptor antagonizes the growth effects of the AT1 receptor:gain-of-function study using gene transfer. Proc Natl Acad Sci USA,1995,92:10663-7.
36. Wu L, Iwai M, Nakagami H et al. Effect of angiotensin Ⅱ type 1 receptor blockade on cardiac remodeling in angiotensin Ⅱ type 2 receptor null mice. Arterioscler Thromb Vasc Biol,2002,22:49-54.
37. Brede M, Roell W, Ritter O et al. Cardiac hypertrophy is associated with decreased eNOS expression in angiotensin AT2 receptor-deficient mice. Hypertension,2003, 42:1177-82.
38. Martin MM and Elton TS. The sequence and genomic organization of the human type 2 angiotensin Ⅱ receptor. Biochem Biophys Res Commun,1995,209:554-62.
39. Bonnardeaux A, Davies E, Jeunemaitre X et al. Angiotensin Ⅱ type 1 receptor gene polymorphisms in human essential hypertension. Hypertension,1994,24:63-9.
40. Kainulainen K, Perola M, Terwilliger J et al. Evidence for involvement of the type 1 angiotensin Ⅱ receptor locus in essential hypertension. Hypertension,1999,33: 844-9.
41. Diez J, Laviades C, Orbe J et al. The A1166C polymorphism of the ATI receptor gene is associated with collagen type I synthesis and myocardial stiffness in hypertensives. J Hypertens,2003,21:2085-92.
42. Zhang Y, Zhang KX, Wang GL et al. Angiotensin Ⅱ type 2 receptor gene polymorphisms and essential hypertension. Acta Pharmacol Sin,2003,24:1089-93.
43. Sauer S, Lechner D, Berlin K et al. A novel procedure for efficient genotyping of single nucleotide polymorphisms. Nucleic Acids Res,2000,28:E13.
44. Takatsu K, Yokomaku T, Kurata S et al. A new approach to SNP genotyping with fluorescently labeled mononucleotides. Nucleic Acids Res,2004,32:e60.
1. Conn JW. Presidential address. Ⅰ. Painting background. Ⅱ. Primary aldosteronism, a new clinical syndrome. J Lab Clin Med,1955,45:3-17.
2. Gordon RD, Stowasser M, Tunny TJ et al. High incidence of primary aldosteronism in 199 patients referred with hypertension. Clin Exp Pharmacol Physiol,1994,21: 315-8.
3. Plouin PF, Amar L and Chatellier G. Trends in the prevalence of primary aldosteronism, aldosterone-producing adenomas, and surgically correctable aldosterone-dependent hypertension. Nephrol Dial Transplant,2004,19:774-7.
4. Loh KC, Koay ES, Khaw MC et al. Prevalence of primary aldosteronism among Asian hypertensive patients in Singapore. J Clin Endocrinol Metab,2000,85: 2854-9.
5. Gallay BJ, Ahmad S, Xu L et al. Screening for primary aldosteronism without discontinuing hypertensive medications:plasma aldosterone-renin ratio. Am J Kidney Dis,2001,37:699-705.
6. Eide IK, Torjesen PA, Drolsum A et al. Low-renin status in therapy-resistant hypertension:a clue to efficient treatment. J Hypertens,2004,22:2217-26.
7. Strauch B, Zelinka T, Hampf M et al. Prevalence of primary hyperaldosteronism in moderate to severe hypertension in the Central Europe region. J Hum Hypertens, 2003,17:349-52.
8. Milliez P, Girerd X, Plouin PF et al. Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol, 2005,45:1243-8.
9. Stewart PM. Mineralocorticoid hypertension. Lancet,1999,353:1341-7.
10. Giacchetti G, Mulatero P, Mantero F et al. Primary aldosteronism, a major form of low renin hypertension:from screening to diagnosis. Trends Endocrinol Metab, 2008,19:104-8.
11. Plouin PF, Rossignol P and Amar L. Selection of patients for surgery for primary aldosteronism. Clin Exp Pharmacol Physiol,2008,35:522-5.
12. Meyer A, Brabant G and Behrend M. Long-term follow-up after adrenalectomy for primary aldosteronism. World J Surg,2005,29:155-9.
13. Lumachi F, Ermani M, Basso SM et al. Long-term results of adrenalectomy in patients with aldosterone-producing adenomas:multivariate analysis of factors affecting unresolved hypertension and review of the literature. Am Surg,2005,71: 864-9.
14. Harris DA, Au-Yong I, Basnyat PS et al. Review of surgical management of aldosterone secreting tumours of the adrenal cortex. Eur J Surg Oncol,2003,29: 467-74.
15. Zarnegar R, Young WF, Jr., Lee J et al. The aldosteronoma resolution score: predicting complete resolution of hypertension after adrenalectomy for aldosteronoma. Ann Surg,2008,247:511-8.
16. de Gasparo M, Catt KJ, Inagami T et al. International union of pharmacology. XXIII. The angiotensin Ⅱ receptors. Pharmacol Rev,2000,52:415-72.
17. Gard PR. The role of angiotensin Ⅱ in cognition and behaviour. Eur J Pharmacol, 2002,438:1-14.
18. McKinley MJ, Albiston AL, Allen AM et al. The brain renin-angiotensin system: location and physiological roles. Int J Biochem Cell Biol,2003,35:901-18.
19. Thomas WG and Mendelsohn FA. Angiotensin receptors:form and function and distribution. Int J Biochem Cell Biol,2003,35:774-9.
20. Widdop RE, Jones ES, Hannan RE et al. Angiotensin AT2 receptors:cardiovascular hope or hype? Br J Pharmacol,2003,140:809-24.
21. Nakajima M, Hutchinson HG, Fujinaga M et al. The angiotensin Ⅱ type 2 (AT2) receptor antagonizes the growth effects of the AT1 receptor:gain-of-function study using gene transfer. Proc Natl Acad Sci USA,1995,92:10663-7.
22. Inagami T, Eguchi S, Numaguchi K et al. Cross-talk between angiotensin Ⅱ receptors and the tyrosine kinases and phosphatases. J Am Soc Nephrol,1999,10 Suppl11:S57-61.
23. Wu L, Iwai M, Nakagami H et al. Effect of angiotensin Ⅱ type 1 receptor blockade on cardiac remodeling in angiotensin Ⅱ type 2 receptor null mice. Arterioscler Thromb Vasc Biol,2002,22:49-54.
24. Xu J, Carretero OA, Liu YH et al. Role of AT2 receptors in the cardioprotective effect of AT1 antagonists in mice. Hypertension,2002,40:244-50.
25. Brede M, Roell W, Ritter O et al. Cardiac hypertrophy is associated with decreased eNOS expression in angiotensin AT2 receptor-deficient mice. Hypertension,2003, 42:1177-82.
26. Oishi Y, Ozono R, Yano Y et al. Cardioprotective role of AT2 receptor in postinfarction left ventricular remodeling. Hypertension,2003,41:814-8.
27. Sawka AM, Young WF, Thompson GB et al. Primary aldosteronism:factors associated with normalization of blood pressure after surgery. Ann Intern Med,2001, 135:258-61.
28. Blumenfeld JD, Sealey JE, Schlussel Y et al. Diagnosis and treatment of primary hyperaldosteronism. Ann Intern Med,1994,121:877-85.
29. Pang TC, Bambach C, Monaghan JC et al. Outcomes of laparoscopic adrenalectomy for hyperaldosteronism. ANZ J Surg,2007,77:768-73.
30. Massien-Simon C, Battaglia C, Chatellier G et al. [Conn's adenoma. Diagnostic and prognostic value of the measurement of potassium, renin, aldosterone levels and the aldosterone/renin ratio]. Presse Med,1995,24:1238-42.
1. Stewart PM. Mineralocorticoid hypertension. Lancet,1999,353:1341-7.
2. Vinson GP, Ho MM and Puddefoot JR. The distribution of angiotensin Ⅱ type 1 receptors, and the tissue renin-angiotensin systems. Mol Med Today,1995,1:35-9.
3. Cook MD, Phillips MI, Cook VI et al. Angiotensin Ⅱ receptor subtypes on adrenal adenoma in primary hyperaldosteronism. J Am Soc Nephrol,1993,4:111-6.
4. Schmieder RE, Erdmann J, Delles C et al. Effect of the angiotensin Ⅱ type 2-receptor gene (+1675 G/A) on left ventricular structure in humans. J Am Coll Cardiol,2001,37:175-82.
5. Alfakih K, Maqbool A, Sivananthan M et al. Left ventricle mass index and the common, functional, X-linked angiotensin Ⅱ type-2 receptor gene polymorphism (-1332 G/A) in patients with systemic hypertension. Hypertension,2004,43: 1189-94.
6. Koh WP, Yuan JM, Van Den Berg D et al. Polymorphisms in angiotensin Ⅱ type 1 receptor and angiotensin I-converting enzyme genes and breast cancer risk among Chinese women in Singapore. Carcinogenesis,2005,26:459-64.
7. de Gasparo M, Catt KJ, Inagami T et al. International union of pharmacology. XXIII. The angiotensin Ⅱ receptors. Pharmacol Rev,2000,52:415-72.
8. Opocher G, Rocco S, Cimolato M et al. Angiotensin Ⅱ receptors in cortical and medullary adrenal tumors. J Clin Endocrinol Metab,1997,82:865-9.
9. Pawlikowski M, Winczyk K and Sledz B. Immunohistochemical detection of angiotensin receptors AT1 and AT2 in adrenal tumors. Folia Histochem Cytobiol, 2008,46:51-5.
10. Nawata H, Takayanagi R, Ohnaka K et al. Type 1 angiotensin Ⅱ receptors of adrenal tumors. Steroids,1995,60:28-34.
11. Schubert B, Fassnacht M, Beuschlein F et al. Angiotensin Ⅱ type 1 receptor and ACTH receptor expression in human adrenocortical neoplasms. Clin Endocrinol (Oxf),2001,54:627-32.
12. Tissir F, Riviere M, Guo DF et al. Localization of the genes encoding the three rat angiotensin Ⅱ receptors, Agtr1a, Agtr1b, Agtr2, and the human AGTR2 receptor respectively to rat chromosomes 17q12,2q24 and Xq34, and the human Xq22. Cytogenet Cell Genet,1995,71:77-80.
13. Martin MM and Elton TS. The sequence and genomic organization of the human type 2 angiotensin Ⅱreceptor. Biochem Biophys Res Commun,1995,209:554-62.
14. Grady EF, Sechi LA, Griffin CA et al. Expression of AT2 receptors in the developing rat fetus. J Clin Invest,1991,88:921-33.
15. Inagami T, Eguchi S, Numaguchi K et al. Cross-talk between angiotensin Ⅱ receptors and the tyrosine kinases and phosphatases. J Am Soc Nephrol,1999,10 Suppl11:S57-61.
16. Nakajima M, Hutchinson HG, Fujinaga M et al. The angiotensin Ⅱ type 2 (AT2) receptor antagonizes the growth effects of the AT1 receptor:gain-of-function study using gene transfer. Proc Natl Acad Sci USA,1995,92:10663-7.
17. Carey RM, Wang ZQ and Siragy HM. Role of the angiotensin type 2 receptor in the regulation of blood pressure and renal function. Hypertension,2000,35:155-63.
18. Huang XC, Richards EM and Sumners C. Mitogen-activated protein kinases in rat brain neuronal cultures are activated by angiotensin Ⅱ type 1 receptors and inhibited by angiotensin Ⅱ type 2 receptors. J Biol Chem,1996,271:15635-41.
19. Horiuchi M, Hayashida W, Akishita M et al. Stimulation of different subtypes of angiotensin Ⅱ receptors, AT1 and AT2 receptors, regulates STAT activation by negative crosstalk. Circ Res,1999,84:876-82.
20. Lehtonen JY, Daviet L, Nahmias C et al. Analysis of functional domains of angiotensin Ⅱ type 2 receptor involved in apoptosis. Mol Endocrinol,1999,13: 1051-60.
21. Wolf G, Harendza S, Schroeder R et al. Angiotensin Ⅱ's antiproliferative effects mediated through AT2-receptors depend on down-regulation of SM-20. Lab Invest, 2002,82:1305-17.
22. Herrmann SM, Nicaud V, Schmidt-Petersen K et al. Angiotensin Ⅱ type 2 receptor gene polymorphism and cardiovascular phenotypes:the GLAECO and GLAOLD studies. Eur J Heart Fail,2002,4:707-12.
23. Jin XQ, Fukuda N, Su JZ et al. Angiotensin Ⅱ type 2 receptor gene transfer downregulates angiotensin Ⅱ type 1a receptor in vascular smooth muscle cells. Hypertension,2002,39:1021-7.
24. Kuznetsova T, Staessen JA, Thijs L et al. Left ventricular mass in relation to genetic variation in angiotensin Ⅱ receptors, renin system genes, and sodium excretion. Circulation,2004,110:2644-50.
25. Nishimura H, Yerkes E, Hohenfellner K et al. Role of the angiotensin type 2 receptor gene in congenital anomalies of the kidney and urinary tract, CAKUT, of mice and men. Mol Cell,1999,3:1-10.
26. Warnecke C, Mugrauer P, Surder D et al. Intronic ANG Ⅱ type 2 receptor gene polymorphism 1675 G/A modulates receptor protein expression but not mRNA splicing. Am J Physiol Regul Integr Comp Physiol,2005,289:R1729-35.
1. de Gasparo M, Catt KJ, Inagami T et al. International union of pharmacology. XXIII. The angiotensin Ⅱ receptors. Pharmacol Rev,2000,52:415-72.
2. Gard PR. The role of angiotensin Ⅱ in cognition and behaviour. Eur J Pharmacol, 2002,438:1-14.
3. McKinley MJ, Albiston AL, Allen AM et al. The brain renin-angiotensin system: location and physiological roles.Int J Biochem Cell Biol,2003,35:901-18.
4. Thomas WG and Mendelsohn FA. Angiotensin receptors:form and function and distribution. Int J Biochem Cell Biol,2003,35:774-9.
5. Speth RC, Thompson SM and Johns SJ. Angiotensin Ⅱ receptors. Structural and functional considerations. Adv Exp Med Biol,1995,377:169-92.
6. de Gasparo M and Siragy HM. The AT2 receptor:fact, fancy and fantasy. Regul Pept,1999,81:11-24.
7. Eguchi S and Inagami T. Signal transduction of angiotensin Ⅱ type 1 receptor through receptor tyrosine kinase. Regul Pept,2000,91:13-20.
8. Saito Y and Berk BC. Angiotensin Ⅱ-mediated signal transduction pathways. Curr Hypertens Rep,2002,4:167-71.
9. Wu Z, Maric C, Roesch DM et al. Estrogen regulates adrenal angiotensin AT1 receptors by modulating AT1 receptor translation. Endocrinology,2003,144: 3251-61.
10. Takekoshi K, Ishii K, Shibuya S et al. Angiotensin Ⅱ type 2 receptor counter-regulates type 1 receptor in catecholamine synthesis in cultured porcine adrenal medullary chromaffin cells. Hypertension,2002,39:142-8.
11. Chow L, Rezmann L, Catt KJ et al. Role of the renin-angiotensin system in prostate cancer. Mol Cell Endocrinol,2009,302:219-29.
12. Martin MM and Elton TS. The sequence and genomic organization of the human type 2 angiotensin Ⅱ receptor. Biochem Biophys Res Commun,1995,209: 554-62.
13. Horiuchi M, Akishita M and Dzau VJ. Recent progress in angiotensin Ⅱ type 2 receptor research in the cardiovascular system. Hypertension,1999,33:613-21.
14. Curnow KM, Pascoe L, Davies E et al. Alternatively spliced human type 1 angiotensin Ⅱ receptor mRNAs are translated at different efficiencies and encode two receptor isoforms. Mol Endocrinol,1995,9:1250-62.
15. Xu K and Murphy TJ. Reconstitution of angiotensin receptor mRNA down-regulation in vascular smooth muscle. Post-transcriptional control by protein kinase a but not mitogenic signaling directed by the 5'-untranslated region. J Biol Chem,2000,275:7604-11.
16. Qian H, Pipolo L and Thomas WG Association of beta-Arrestin 1 with the type 1A angiotensin Ⅱ receptor involves phosphorylation of the receptor carboxyl terminus and correlates with receptor internalization. Mol Endocrinol,2001,15: 1706-19.
17. Sasaki K, Yamano Y, Bardhan S et al. Cloning and expression of a complementary DNA encoding a bovine adrenal angiotensin Ⅱ type-1 receptor. Nature,1991,351: 230-3.
18. Murphy TJ, Alexander RW, Griendling KK et al. Isolation of a cDNA encoding the vascular type-1 angiotensin Ⅱ receptor. Nature,1991,351:233-6.
19. Sandberg K, Ji H, Clark AJ et al. Cloning and expression of a novel angiotensin Ⅱ receptor subtype. J Biol Chem,1992,267:9455-8.
20. Sasamura H, Hein L, Krieger JE et al. Cloning, characterization, and expression of two angiotensin receptor (AT-1) isoforms from the mouse genome. Biochem Biophys Res Commun,1992,185:253-9.
21. Konishi H, Kuroda S, Inada Y et al. Novel subtype of human angiotensin Ⅱ type 1 receptor:cDNA cloning and expression. Biochem Biophys Res Commun,1994, 199:467-74.
22. Iwai N, Inagami T, Ohmichi N et al. Differential regulation of rat AT 1a and AT1b receptor mRNA. Biochem Biophys Res Commun,1992,188:298-303.
23. Gasc JM, Shanmugam S, Sibony M et al. Tissue-specific expression of type 1 angiotensin II receptor subtypes. An in situ hybridization study. Hypertension, 1994,24:531-7.
24. Audoly LP, Oliverio MI and Coffman TM. Insights into the functions of type 1 (AT1) angiotensin Ⅱ receptors provided by gene targeting. Trends Endocrinol Metab,2000,11:263-9.
25. Eguchi S, Dempsey PJ, Frank GD et al. Activation of MAPKs by angiotensin Ⅱ in vascular smooth muscle cells. Metalloprotease-dependent EGF receptor activation is required for activation of ERK and p38 MAPK but not for JNK. J Biol Chem, 2001,276:7957-62.
26. Thomas WG, Brandenburger Y, Autelitano DJ et al. Adenoviral-directed expression of the type 1A angiotensin receptor promotes cardiomyocyte hypertrophy via transactivation of the epidermal growth factor receptor. Circ Res, 2002,90:135-42.
27. Asakura M, Kitakaze M, Takashima S et al. Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF:metalloproteinase inhibitors as a new therapy. Nat Med,2002,8:35-40.
28. Gomez RA, Lynch KR, Chevalier RL et al. Renin and angiotensinogen gene expression in maturing rat kidney. Am J Physiol,1988,254:F582-7.
29. Kakuchi J, Ichiki T, Kiyama S et al. Developmental expression of renal angiotensin Ⅱ receptor genes in the mouse. Kidney Int,1995,47:140-7.
30. Kim HS, Krege JH, Kluckman KD et al. Genetic control of blood pressure and the angiotensinogen locus. Proc Natl Acad Sci USA,1995,92:2735-9.
31. Matsusaka T, Nishimura H, Utsunomiya H et al. Chimeric mice carrying'regional' targeted deletion of the angiotensin type 1A receptor gene. Evidence against the role for local angiotensin in the in vivo feedback regulation of renin synthesis in juxtaglomerular cells. J Clin Invest,1996,98:1867-77.
32. Ito M, Oliverio MI, Mannon PJ et al. Regulation of blood pressure by the type 1A angiotensin Ⅱ receptor gene. Proc Natl Acad Sci USA,1995,92:3521-5.
33. Ichiki T, Labosky PA, Shiota C et al. Effects on blood pressure and exploratory behaviour of mice lacking angiotensin Ⅱ type-2 receptor. Nature,1995,377: 748-50.
34. Hein L, Barsh GS, Pratt RE et al. Behavioural and cardiovascular effects of disrupting the angiotensin Ⅱ type-2 receptor in mice. Nature,1995,377:744-7.
35. Oliverio MI, Kim HS, Ito M et al. Reduced growth, abnormal kidney structure, and type 2 (AT2) angiotensin receptor-mediated blood pressure regulation in mice lacking both AT1A and AT1B receptors for angiotensin Ⅱ. Proc Natl Acad Sci U S A,1998,95:15496-501.
36. Chen X, Li W, Yoshida H et al. Targeting deletion of angiotensin type 1B receptor gene in the mouse. Am J Physiol,1997,272:F299-304.
37. Tsuchida S, Matsusaka T, Chen X et al. Murine double nullizygotes of the angiotensin type 1A and 1B receptor genes duplicate severe abnormal phenotypes of angiotensinogen nullizygotes. J Clin Invest,1998,101:755-60.
38. MacTaggart TE, Ito M, Smithies O et al. Mouse angiotensin receptor genes Agtrla and Agtrlb map to chromosomes 13 and 3. Mamm Genome,1997,8:294-5.
39. Krege JH, John SW, Langenbach LL et al. Male-female differences in fertility and blood pressure in ACE-deficient mice. Nature,1995,375:146-8.
40. Benetos A, Topouchian J, Ricard S et al. Influence of angiotensin Ⅱ type 1 receptor polymorphism on aortic stiffness in never-treated hypertensive patients. Hypertension,1995,26:44-7.
41. Bonnardeaux A, Davies E, Jeunemaitre X et al. Angiotensin Ⅱ type 1 receptor gene polymorphisms in human essential hypertension. Hypertension,1994,24: 63-9.
42. Oliverio MI, Best CF, Kim HS et al. Angiotensin Ⅱ responses in AT1A receptor-deficient mice:a role for AT1B receptors in blood pressure regulation. Am J Physiol,1997,272:F515-20.
43. Ichikawa I and Brenner BM. Importance of efferent arteriolar vascular tone in regulation of proximal tubule fluid reabsorption and glomerulotubular balance in the rat. J Clin Invest,1980,65:1192-201.
44. Schuster VL, Kokko JP and Jacobson HR. Angiotensin Ⅱ directly stimulates sodium transport in rabbit proximal convoluted tubules. J Clin Invest,1984,73: 507-15.
45. Kojima I, Kojima K, Kreutter D et al. The temporal integration of the aldosterone secretory response to angiotensin occurs via two intracellular pathways. J Biol Chem,1984,259:14448-57.
46. Oliverio MI, Best CF, Smithies O et al. Regulation of sodium balance and blood pressure by the AT(1A) receptor for angiotensin Ⅱ. Hypertension,2000,35:550-4.
47. Timmermans PB, Wong PC, Chiu AT et al. Angiotensin Ⅱ receptors and angiotensin Ⅱreceptor antagonists. Pharmacol Rev,1993,45:205-51.
48. Okubo S, Niimura F, Nishimura H et al. Angiotensin-independent mechanism for aldosterone synthesis during chronic extracellular fluid volume depletion. J Clin Invest,1997,99:855-60.
49. Phillips MI. Functions of angiotensin in the central nervous system. Annu Rev Physiol,1987,49:413-35.
50. Oliverio MI, Delnomdedieu M, Best CF et al. Abnormal water metabolism in mice lacking the type 1A receptor for ANGⅡ. Am J Physiol Renal Physiol,2000, 278:F75-82.
51. Bankir L and de Rouffignac C. Urinary concentrating ability:insights from comparative anatomy. Am J Physiol,1985,249:R643-66.
52. Baker KM, Booz GW and Dostal DE. Cardiac actions of angiotensinⅡ:Role of an intracardiac renin-angiotensin system. Annu Rev Physiol,1992,54:227-41.
53. Rockman HA, Wachhorst SP, Mao L et al. ANG Ⅱ receptor blockade prevents ventricular hypertrophy and ANF gene expression with pressure overload in mice. Am J Physiol,1994,266:H2468-75.
54. Kudoh S, Komuro I, Hiroi Y et al Mechanical stretch induces hypertrophic responses in cardiac myocytes of angiotensin Ⅱtype 1a receptor knockout mice. J Biol Chem,1998,273:24037-43.
55. Hamawaki M, Coffman TM, Lashus A et al. Pressure-overload hypertrophy is unabated in mice devoid of AT1A receptors. Am J Physiol,1998,274:H868-73.
56. Harada K, Komuro I, Shiojima I et al. Pressure overload induces cardiac hypertrophy in angiotensin Ⅱ type 1A receptor knockout mice. Circulation,1998, 97:1952-9.
57. Matsusaka T, Katori H, Inagami T et al. Communication between myocytes and fibroblasts in cardiac remodeling in angiotensin chimeric mice. J Clin Invest,1999, 103:1451-8.
58. Harada K, Komuro I, Hayashi D et al. Angiotensin Ⅱ type 1a receptor is involved in the occurrence of reperfusion arrhythmias. Circulation,1998,97:315-7.
59. Horiuchi M, Hayashida W, Kambe T et al. Angiotensin type 2 receptor dephosphorylates Bcl-2 by activating mitogen-activated protein kinase phosphatase-1 and induces apoptosis. J Biol Chem,1997,272:19022-6.
60. Bedecs K, Elbaz N, Sutren M et al. Angiotensin Ⅱ type 2 receptors mediate inhibition of mitogen-activated protein kinase cascade and functional activation of SHP-1 tyrosine phosphatase. Biochem J,1997,325 (Pt 2):449-54.
61. Huang XC, Richards EM and Sumners C. Mitogen-activated protein kinases in rat brain neuronal cultures are activated by angiotensin Ⅱ type 1 receptors and inhibited by angiotensin Ⅱ type 2 receptors. J Biol Chem,1996,271:15635-41.
62. Akishita M, Ito M, Lehtonen JY et al. Expression of the AT2 receptor developmentally programs extracellular signal-regulated kinase activity and influences fetal vascular growth. J Clin Invest,1999,103:63-71.
63. Fischer TA, Singh K, O'Hara DS et al. Role of AT1 and AT2 receptors in regulation of MAPKs and MKP-1 by ANG Ⅱ in adult cardiac myocytes. Am J Physiol,1998,275:H906-16.
64. Horiuchi M, Hayashida W, Akishita M et al. Stimulation of different subtypes of angiotensin Ⅱ receptors, AT1 and AT2 receptors, regulates STAT activation by negative crosstalk. Circ Res,1999,84:876-82.
65. Elbaz N, Bedecs K, Masson M et al. Functional trans-inactivation of insulin receptor kinase by growth-inhibitory angiotensin ⅡAT2 receptor. Mol Endocrinol, 2000,14:795-804.
66. Shenoy UV, Richards EM, Huang XC et al. Angiotensin Ⅱ type 2 receptor-mediated apoptosis of cultured neurons from newborn rat brain. Endocrinology,1999,140:500-9.
67. Lehtonen JY, Daviet L, Nahmias C et al. Analysis of functional domains of angiotensin Ⅱ type 2 receptor involved in apoptosis. Mol Endocrinol,1999,13: 1051-60.
68. Dimmeler S, Rippmann V, Weiland U et al. Angiotensin Ⅱ induces apoptosis of human endothelial cells. Protective effect of nitric oxide. Circ Res,1997,81: 970-6.
69. Gallinat S, Busche S, Schutze S et al. AT2 receptor stimulation induces generation of ceramides in PC12W cells. FEBS Lett,1999,443:75-9.
70. Siragy HM, Inagami T, Ichiki T et al. Sustained hypersensitivity to angiotensin Ⅱ and its mechanism in mice lacking the subtype-2 (AT2) angiotensin receptor. Proc Natl Acad Sci USA,1999,96:6506-10.
71. Siragy HM and Carey RM. The subtype 2 (AT2) angiotensin receptor mediates renal production of nitric oxide in conscious rats. J Clin Invest,1997,100:264-9.
72. Gohlke P, Pees C and Unger T. AT2 receptor stimulation increases aortic cyclic GMP in SHRSP by a kinin-dependent mechanism. Hypertension,1998,31: 349-55.
73. Jiao H, Cui XL, Torti M et al. Arachidonic acid mediates angiotensin Ⅱ effects on p21ras in renal proximal tubular cells via the tyrosine kinase-Shc-Grb2-Sos pathway. Proc Natl Acad Sci U SA,1998,95:7417-21.
74. Dulin NO, Alexander LD, Harwalkar S et al. Phospholipase A2-mediated activation of mitogen-activated protein kinase by angiotensin Ⅱ. Proc Natl Acad Sci USA,1998,95:8098-102.
75. Lokuta AJ, Cooper C, Gaa ST et al. Angiotensin Ⅱ stimulates the release of phospholipid-derived second messengers through multiple receptor subtypes in heart cells. J Biol Chem,1994,269:4832-8.
76. Buisson B, Laflamme L, Bottari SP et al. A G protein is involved in the angiotensin AT2 receptor inhibition of the T-type calcium current in non-differentiated NG108-15 cells. J Biol Chem,1995,270:1670-4.
77. Zhu M, Gelband CH, Moore JM et al. Angiotensin Ⅱ type 2 receptor stimulation of neuronal delayed-rectifier potassium current involves phospholipase A2 and arachidonic acid. J Neurosci,1998,18:679-86.
78. Laflamme L, Gasparo M, Gallo JM et al. Angiotensin Ⅱ induction of neurite outgrowth by AT2 receptors in NG108-15 cells. Effect counteracted by the AT1 receptors. J Biol Chem,1996,271:22729-35.
79. Stroth U, Meffert S, Gallinat S et al. Angiotensin Ⅱ and NGF differentially influence microtubule proteins in PC12W cells:role of the AT2 receptor. Brain Res Mol Brain Res,1998,53:187-95.
80. Gendron L, Laflamme L, Rivard N et al. Signals from the AT2 (angiotensin type 2) receptor of angiotensin Ⅱ inhibit p21ras and activate MAPK (mitogen-activated protein kinase) to induce morphological neuronal differentiation in NG108-15 cells. Mol Endocrinol,1999,13:1615-26.
81. Cote F, Laflamme L, Payet MD et al. Nitric oxide, a new second messenger involved in the action of angiotensin Ⅱ on neuronal differentiation of NG108-15 cells. Endocr Res,1998,24:403-7.
82. Christopoulos A and El-Fakahany EE. The generation of nitric oxide by G protein-coupled receptors. Life Sci,1999,64:1-15.
83. Parenti A, Morbidelli L, Cui XL et al. Nitric oxide is an upstream signal of vascular endothelial growth factor-induced extracellular signal-regulated kinasel/2 activation in postcapillary endothelium. J Biol Chem,1998,273: 4220-6.
84. Masaki H, Kurihara T, Yamaki A et al. Cardiac-specific overexpression of angiotensin Ⅱ AT2 receptor causes attenuated response to AT1 receptor-mediated pressor and chronotropic effects. J Clin Invest,1998,101:527-35.
85. Liu KL, Lo M, Grouzmann E et al. The subtype 2 of angiotensin Ⅱ receptors and pressure-natriuresis in adult rat kidneys. Br J Pharmacol,1999,126:826-32.
86. Yoshimura Y, Karube M, Aoki H et al. Angiotensin Ⅱ induces ovulation and oocyte maturation in rabbit ovaries via the AT2 receptor subtype. Endocrinology, 1996,137:1204-11.
87. Kotani E, Sugimoto M, Kamata H et al. Biological roles of angiotensin Ⅱ via its type 2 receptor during rat follicle atresia. Am J Physiol,1999,276:E25-33.
88. Okuyama S, Sakagawa T, Chaki S et al. Anxiety-like behavior in mice lacking the angiotensin Ⅱ type-2 receptor. Brain Res,1999,821:150-9.
89. Watanabe T, Hashimoto M, Okuyama S et al. Effects of targeted disruption of the mouse angiotensin II type 2 receptor gene on stress-induced hyperthermia. J Physiol,1999,515 (Pt 3):881-5.
90. Lucius R, Gallinat S, Rosenstiel P et al. The angiotensin Ⅱ type 2 (AT2) receptor promotes axonal regeneration in the optic nerve of adult rats. J Exp Med,1998, 188:661-70.
91. Levy BI, Benessiano J, Henrion D et al. Chronic blockade of AT2-subtype receptors prevents the effect of angiotensin Ⅱ on the rat vascular structure. J Clin Invest,1996,98:418-25.
92. Bartunek J, Weinberg EO, Tajima M et al. Angiotensin Ⅱ type 2 receptor blockade amplifies the early signals of cardiac growth response to angiotensin Ⅱ in hypertrophied hearts. Circulation,1999,99:22-5.
93. Ohkubo N, Matsubara H, Nozawa Y et al. Angiotensin type 2 receptors are reexpressed by cardiac fibroblasts from failing myopathic hamster hearts and inhibit cell growth and fibrillar collagen metabolism. Circulation,1997,96: 3954-62.
94. Ma J, Nishimura H, Fogo A et al. Accelerated fibrosis and collagen deposition develop in the renal interstitium of angiotensin type 2 receptor null mutant mice during ureteral obstruction. Kidney Int,1998,53:937-44.
95. Morrissey JJ and Klahr S. Effect of AT2 receptor blockade on the pathogenesis of renal fibrosis. Am J Physiol,1999,276:F39-45.
96. Nishimura H, Yerkes E, Hohenfellner K et al. Role of the angiotensin type 2 receptor gene in congenital anomalies of the kidney and urinary tract, CAKUT, of mice and men. Mol Cell,1999,3:1-10.
97. Miura S and Karnik SS. Ligand-independent signals from angiotensin Ⅱ type 2 receptor induce apoptosis. Embo J,2000,19:4026-35.
98. Jin XQ, Fukuda N, Su JZ et al. Angiotensin Ⅱ type 2 receptor gene transfer downregulates angiotensin Ⅱ type 1a receptor in vascular smooth muscle cells. Hypertension,2002,39:1021-7.
99. Su JZ, Fukuda N, Jin XQ et al. Effect of AT2 receptor on expression of AT1 and TGF-beta receptors in VSMCs from SHR. Hypertension,2002,40:853-8.
100. D'Amore A, Black MJ and Thomas WG The angiotensin Ⅱtype 2 receptor causes constitutive growth of cardiomyocytes and does not antagonize angiotensin Ⅱ type 1 receptor-mediated hypertrophy. Hypertension,2005,46:1347-54.
101. Falcon BL, Veerasingham SJ, Sumners C et al. Angiotensin Ⅱ type 2 receptor-mediated gene expression profiling in human coronary artery endothelial cells. Hypertension,2005,45:692-7.
102. Unger T, Chung O, Csikos T et al. Angiotensin receptors. J Hypertens Suppl,1996, 14:S95-103.
103. Simon G, Illyes G and Csiky B. Structural vascular changes in hypertension:role of angiotensin Ⅱ, dietary sodium supplementation, blood pressure, and time. Hypertension,1998,32:654-60.
104. Weber KT. Extracellular matrix remodeling in heart failure:a role for de novo angiotensin Ⅱ generation. Circulation,1997,96:4065-82.
105. Widdop RE, Jones ES, Hannan RE et al. Angiotensin AT2 receptors: cardiovascular hope or hype? Br J Pharmacol,2003,140:809-24.
106. Scheuer DA and Perrone MH. Angiotensin type 2 receptors mediate depressor phase of biphasic pressure response to angiotensin. Am J Physiol,1993,264: R917-23.
107. Munzenmaier DH and Greene AS. Opposing actions of angiotensin Ⅱ on microvascular growth and arterial blood pressure. Hypertension,1996,27:760-5.
108. Li XC and Widdop RE. AT2 receptor-mediated vasodilatation is unmasked by AT1 receptor blockade in conscious SHR. Br J Pharmacol,2004,142:821-30.
109. Li H, Gao Y, Grobe JL et al. Potentiation of the antihypertensive action of losartan by peripheral overexpression of the ANG Ⅱ type 2 receptor. Am J Physiol Heart Circ Physiol,2007,292:H727-35.
110. Hiyoshi H, Yayama K, Takano M et al. Stimulation of cyclic GMP production via AT2 and B2 receptors in the pressure-overloaded aorta after banding. Hypertension,2004,43:1258-63.
111. Yayama K, Horii M, Hiyoshi H et al. Up-regulation of angiotensin Ⅱ type 2 receptor in rat thoracic aorta by pressure-overload. J Pharmacol Exp Ther,2004, 308:736-43.
112. Yayama K, Hiyoshi H, Imazu D et al. Angiotensin Ⅱ stimulates endothelial NO synthase phosphorylation in thoracic aorta of mice with abdominal aortic banding via type 2 receptor. Hypertension,2006,48:958-64.
113. Savoia C, Ebrahimian T, He Y et al. Angiotensin Ⅱ/AT2 receptor-induced vasodilation in stroke-prone spontaneously hypertensive rats involves nitric oxide and cGMP-dependent protein kinase. J Hypertens,2006,24:2417-22.
114. Hiyoshi H, Yayama K, Takano M et al. Angiotensin type 2 receptor-mediated phosphorylation of eNOS in the aortas of mice with 2-kidney,1-clip hypertension. Hypertension,2005,45:967-73.
115. Savoia C, Tabet F, Yao G et al. Negative regulation of RhoA/Rho kinase by angiotensin Ⅱ type 2 receptor in vascular smooth muscle cells:role in angiotensin Ⅱ-induced vasodilation in stroke-prone spontaneously hypertensive rats. J Hypertens,2005,23:1037-45.
116. Savoia C, Touyz RM, Volpe M et al. Angiotensin type 2 receptor in resistance arteries of type 2 diabetic hypertensive patients. Hypertension,2007,49:341-6.
117. You D, Loufrani L, Baron C et al. High blood pressure reduction reverses angiotensin Ⅱ type 2 receptor-mediated vasoconstriction into vasodilation in spontaneously hypertensive rats. Circulation,2005,111:1006-11.
118. Booz GW. Cardiac angiotensin AT2 receptor:what exactly does it do? Hypertension,2004,43:1162-3.
119. Regitz-Zagrosek V, Friedel N, Heymann A et al. Regulation, chamber localization, and subtype distribution of angiotensin Ⅱ receptors in human hearts. Circulation, 1995,91:1461-71.
120. Asano K, Dutcher DL, Port JD et al. Selective downregulation of the angiotensin Ⅱ AT1-receptor subtype in failing human ventricular myocardium. Circulation, 1997,95:1193-200.
121. Haywood GA, Gullestad L, Katsuya T et al. AT1 and AT2 angiotensin receptor gene expression in human heart failure. Circulation,1997,95:1201-6.
122. Tsutsumi Y, Matsubara H, Ohkubo N et al. Angiotensin Ⅱ type 2 receptor is upregulated in human heart with interstitial fibrosis, and cardiac fibroblasts are the major cell type for its expression. Circ Res,1998,83:1035-46.
123. Wharton J, Morgan K, Rutherford RA et al. Differential distribution of angiotensin AT2 receptors in the normal and failing human heart. J Pharmacol Exp Ther,1998,284:323-36.
124. Brede M, Roell W, Ritter O et al. Cardiac hypertrophy is associated with decreased eNOS expression in angiotensin AT2 receptor-deficient mice. Hypertension,2003,42:1177-82.
125. Oishi Y, Ozono R, Yano Y et al. Cardioprotective role of AT2 receptor in postinfarction left ventricular remodeling. Hypertension,2003,41:814-8.
126. Xu J, Carretero OA, Liu YH et al. Role of AT2 receptors in the cardioprotective effect of AT1 antagonists in mice. Hypertension,2002,40:244-50.
127. Yan X, Price RL, Nakayama M et al. Ventricular-specific expression of angiotensin Ⅱ type 2 receptors causes dilated cardiomyopathy and heart failure in transgenic mice. Am J Physiol Heart Circ Physiol,2003,285:H2179-87.
128. Senbonmatsu T, Ichihara S, Price E, Jr. et al. Evidence for angiotensinⅡtype 2 receptor-mediated cardiac myocyte enlargement during in vivo pressure overload. J Clin Invest,2000,106:R1-5.
129. Ichihara S, Senbonmatsu T, Price E, Jr. et al. Angiotensin Ⅱ type 2 receptor is essential for left ventricular hypertrophy and cardiac fibrosis in chronic angiotensin Ⅱ-induced hypertension. Circulation,2001,104:346-51.
130. Ichihara S, Senbonmatsu T, Price E, Jr. et al. Targeted deletion of angiotensin Ⅱ type 2 receptor caused cardiac rupture after acute myocardial infarction. Circulation,2002,106:2244-9.
131. Lako-Futo Z, Szokodi I, Sarman B et al. Evidence for a functional role of angiotensin Ⅱ type 2 receptor in the cardiac hypertrophic process in vivo in the rat heart. Circulation,2003,108:2414-22.
132. Yang Z, Bove CM, French BA et al. Angiotensin Ⅱtype 2 receptor overexpression preserves left ventricular function after myocardial infarction. Circulation,2002, 106:106-11.
133. Bove CM, Gilson WD, Scott CD et al. The angiotensin Ⅱ type 2 receptor and improved adjacent region function post-MI. J Cardiovasc Magn Reson,2005,7: 459-64.
134. Bove CM, Yang Z, Gilson WD et al. Nitric oxide mediates benefits of angiotensin Ⅱ type 2 receptor overexpression during post-infarct remodeling. Hypertension, 2004,43:680-5.
135. Liu YH, Yang XP, Sharov VG et al. Effects of angiotensin-converting enzyme inhibitors and angiotensin Ⅱ type 1 receptor antagonists in rats with heart failure. Role of kinins and angiotensin Ⅱ type 2 receptors. J Clin Invest,1997,99: 1926-35.
136. Isbell DC, Voros S, Yang Z et al. Interaction between bradykinin subtype 2 and angiotensin Ⅱ type 2 receptors during post-MI left ventricular remodeling. Am J Physiol Heart Circ Physiol,2007,293:H3372-8.
137. Wu L, Iwai M, Nakagami H et al. Effect of angiotensin Ⅱ type 1 receptor blockade on cardiac remodeling in angiotensin Ⅱ type 2 receptor null mice. Arterioscler Thromb Vasc Biol,2002,22:49-54.
138. Brilla CG, Zhou G, Matsubara L et al. Collagen metabolism in cultured adult rat cardiac fibroblasts:response to angiotensin Ⅱ and aldosterone. J Mol Cell Cardiol, 1994,26:809-20.
139. Brilla CG, Zhou G, Rupp H et al. Role of angiotensin Ⅱ and prostaglandin E2 in regulating cardiac fibroblast collagen turnover. Am J Cardiol,1995,76:8D-13D.
140. Brassard P, Amiri F and Schiffrin EL. Combined angiotensin Ⅱ type 1 and type 2 receptor blockade on vascular remodeling and matrix metalloproteinases in resistance arteries. Hypertension,2005,46:598-606.
141. Lijnen PJ, Petrov VV and Fagard RH. Induction of cardiac fibrosis by angiotensin II. Methods Find Exp Clin Pharmacol,2000,22:709-23.
142. Touyz RM, He Q El Mabrouk M et al. p38 Map kinase regulates vascular smooth muscle cell collagen synthesis by angiotensin Ⅱ in SHR but not in WKY. Hypertension,2001,37:574-80.
143. Warnecke C, Kaup D, Marienfeld U et al. Adenovirus-mediated overexpression and stimulation of the human angiotensin II type 2 receptor in porcine cardiac fibroblasts does not modulate proliferation, collagen I mRNA expression and ERK1/ERK2 activity, but inhibits protein tyrosine phosphatases. J Mol Med,2001, 79:510-21.
144. Ito T, Yamakawa H, Bregonzio C et al. Protection against ischemia and improvement of cerebral blood flow in genetically hypertensive rats by chronic pretreatment with an angiotensin Ⅱ AT1 antagonist. Stroke,2002,33:2297-303.
145. Walther T, Olah L, Harms C et al. Ischemic injury in experimental stroke depends on angiotensin Ⅱ. Faseb J,2002,16:169-76.
146. Nishimura Y, Ito T and Saavedra JM. Angiotensin Ⅱ AT(1) blockade normalizes cerebrovascular autoregulation and reduces cerebral ischemia in spontaneously hypertensive rats. Stroke,2000,31:2478-86.
147. Saavedra JM, Benicky J and Zhou J. Mechanisms of the Anti-Ischemic Effect of Angiotensin Ⅱ AT(1) Receptor Antagonists in the Brain. Cell Mol Neurobiol, 2006,26:1099-111.
148. Zhu YZ, Chimon GN, Zhu YC et al. Expression of angiotensin Ⅱ AT2 receptor in the acute phase of stroke in rats. Neuroreport,2000,11:1191-4.
149. Li J, Culman J, Hortnagl H et al. Angiotensin AT2 receptor protects against cerebral ischemia-induced neuronal injury. Faseb J,2005,19:617-9.
150. Lu Q, Zhu YZ and Wong PT. Neuroprotective effects of candesartan against cerebral ischemia in spontaneously hypertensive rats. Neuroreport,2005,16: 1963-7.
151. Mogi M, Li JM, Iwanami J et al. Angiotensin Ⅱ type-2 receptor stimulation prevents neural damage by transcriptional activation of methyl methanesulfonate sensitive 2. Hypertension,2006,48:141-8.
152. Iwai M, Liu HW, Chen R et al. Possible inhibition of focal cerebral ischemia by angiotensin Ⅱ type 2 receptor stimulation. Circulation,2004,110:843-8.
153. Grammatopoulos T, Morris K, Ferguson P et al. Angiotensin protects cortical neurons from hypoxic-induced apoptosis via the angiotensin type 2 receptor. Brain Res Mol Brain Res,2002,99:114-24.
154. Reinecke K, Lucius R, Reinecke A et al. Angiotensin Ⅱ accelerates functional recovery in the rat sciatic nerve in vivo:role of the AT2 receptor and the transcription factor NF-kappaB. Faseb J,2003,17:2094-6.
155. Hein L, Meinel L, Pratt RE et al. Intracellular trafficking of angiotensin Ⅱ and its AT1 and AT2 receptors:evidence for selective sorting of receptor and ligand. Mol Endocrinol,1997,11:1266-77.
156. Doria A, Onuma T, Warram JH et al. Synergistic effect of angiotensin Ⅱ type 1 receptor genotype and poor glycaemic control on risk of nephropathy in IDDM. Diabetologia,1997,40:1293-9.
157. Chaves FJ, Pascual JM, Rovira E et al. Angiotensin Ⅱ AT1 receptor gene polymorphism and microalbuminuria in essential hypertension. Am J Hypertens, 2001,14:364-70.
158. Erdmann J, Riedel K, Rohde K et al. Characterization of polymorphisms in the promoter of the human angiotensin Ⅱ subtype 1 (AT1) receptor gene. Ann Hum Genet,1999,63:369-74.
159. Poirier O, Georges JL, Ricard S et al. New polymorphisms of the angiotensin Ⅱ type 1 receptor gene and their associations with myocardial infarction and blood pressure:the ECTIM study. Etude Cas-Temoin de l'Infarctus du Myocarde. J Hypertens,1998,16:1443-7.
160. Takahashi N, Murakami H, Kodama K et al. Association of a polymorphism at the 5'-region of the angiotensin Ⅱ type 1 receptor with hypertension. Ann Hum Genet, 2000,64:197-205.
161. Zhu X, Chang YP, Yan D et al. Associations between hypertension and genes in the renin-angiotensin system. Hypertension,2003,41:1027-34.
162. Lajemi M, Labat C, Gautier S et al. Angiotensin Ⅱ type 1 receptor-153 A/G and 1166A/C gene polymorphisms and increase in aortic stiffness with age in hypertensive subjects. J Hypertens,2001,19:407-13.
163. Kainulainen K, Perola M, Terwilliger J et al. Evidence for involvement of the type 1 angiotensin Ⅱ receptor locus in essential hypertension. Hypertension,1999,33: 844-9.
164. Wang WY, Zee RY and Morris BJ. Association of angiotensin II type 1 receptor gene polymorphism with essential hypertension. Clin Genet,1997,51:31-4.
165. Kobashi G, Hata A, Ohta K et al. A1166C variant of angiotensin Ⅱ type 1 receptor gene is associated with severe hypertension in pregnancy independently of T235 variant of angiotensinogen gene. J Hum Genet,2004,49:182-6.
166. Wang JG and Staessen JA. Genetic polymorphisms in the renin-angiotensin system:relevance for susceptibility to cardiovascular disease. Eur J Pharmacol, 2000,410:289-302.
167. Henskens LH, Spiering W, Stoffers HE et al. Effects of ACE I/D and AT1R-A1166C polymorphisms on blood pressure in a healthy normotensive primary care population:first results of the Hippocates study. J Hypertens,2003, 21:81-6.
168. Jiang Z, Zhao W, Yu F et al. Association of angiotensin Ⅱ type 1 receptor gene polymorphism with essential hypertension. Chin Med J (Engl),2001,114: 1249-51.
169. Ono K, Mannami T, Baba S et al. Lack of association between angiotensin Ⅱ type 1 receptor gene polymorphism and hypertension in Japanese. Hypertens Res,2003, 26:131-4.
170. Iliadou A, Lichtenstein P, Morgenstern R et al. Repeated blood pressure measurements in a sample of Swedish twins:heritabilities and associations with polymorphisms in the renin-angiotensin-aldosterone system. J Hypertens,2002, 20:1543-50.
171. Schmidt S, Beige J, Walla-Friedel M et al. A polymorphism in the gene for the angiotensin Ⅱtype 1 receptor is not associated with hypertension. J Hypertens, 1997,15:1385-8.
172. Tiret L, Blanc H, Ruidavets JB et al. Gene polymorphisms of the renin-angiotensin system in relation to hypertension and parental history of myocardial infarction and stroke:the PEGASE study. Projet d'Etude des Genes de 1'Hypertension Arterielle Severe a moderee Essentielle. J Hypertens,1998,16: 37-44.
173. Sierra C, Coca A, Gomez-Angelats E et al. Renin-angiotensin system genetic polymorphisms and cerebral white matter lesions in essential hypertension. Hypertension,2002,39:343-7.
174. Buraczynska M, Ksiazek P, Zaluska W et al. Angiotensin Ⅱ type 1 receptor gene polymorphism in end-stage renal disease. Nephron,2002,92:51-5.
175. Coll E, Campos B, Gonzalez-Nunez D et al. Association between the A1166C polymorphism of the angiotensin Ⅱ receptor type 1 and progression of chronic renal insufficiency. J Nephrol,2003,16:357-64.
176. Benetos A, Cambien F, Gautier S et al. Influence of the angiotensin Ⅱ type 1 receptor gene polymorphism on the effects of perindopril and nitrendipine on arterial stiffness in hypertensive individuals. Hypertension,1996,28:1081-4.
177. Benetos A, Gautier S, Ricard S et al. Influence of angiotensin-converting enzyme and angiotensin Ⅱ type 1 receptor gene polymorphisms on aortic stiffness in normotensive and hypertensive patients. Circulation,1996,94:698-703.
178. Girerd X, Hanon O, Mourad JJ et al. Lack of association between renin-angiotensin system, gene polymorphisms, and wall thickness of the radial and carotid arteries. Hypertension,1998,32:579-83.
179. Diez J, Laviades C, Orbe J et al. The A1166C polymorphism of the AT1 receptor gene is associated with collagen type Ⅰ synthesis and myocardial stiffness in hypertensives. J Hypertens,2003,21:2085-92.
180. Andersson B, Blange I and Sylven C. Angiotensin-Ⅱ type 1 receptor gene polymorphism and long-term survival in patients with idiopathic congestive heart failure. Eur J Heart Fail,1999,1:363-9.
181. Jin W, Liu Y, Sheng HH et al. Single nucleotide polymorphisms in promoter of angiotensin Ⅱ type 1 receptor gene associated with essential hypertension and coronary heart disease in Chinese population. Acta Pharmacol Sin,2003,24: 1083-8.
182. Koh WP, Yuan JM, Van Den Berg D et al. Polymorphisms in angiotensin Ⅱ type 1 receptor and angiotensin I-converting enzyme genes and breast cancer risk among Chinese women in Singapore. Carcinogenesis,2005,26:459-64.
183. Deinum J, van Gool JM, Kofflard MJ et al. Angiotensin Ⅱ type 2 receptors and cardiac hypertrophy in women with hypertrophic cardiomyopathy. Hypertension, 2001,38:1278-81.
184. Delles C, Erdmann J, Jacobi J et al. Lack of association between polymorphisms of angiotensin Ⅱ receptor genes and response to short-term angiotensin Ⅱ infusion. J Hypertens,2000,18:1573-8.
185. Zhang Y, Zhang KX, Wang GL et al. Angiotensin Ⅱ type 2 receptor gene polymorphisms and essential hypertension. Acta Pharmacol Sin,2003,24: 1089-93.
186. Alfakih K, Maqbool A, Sivananthan M et al. Left ventricle mass index and the common, functional, X-linked angiotensin Ⅱ type-2 receptor gene polymorphism (-1332 G/A) in patients with systemic hypertension. Hypertension,2004,43: 1189-94.
187. Schmieder RE, Erdmann J, Delles C et al. Effect of the angiotensin Ⅱ type 2-receptor gene (+1675 G/A) on left ventricular structure in humans. J Am Coll Cardiol,2001,37:175-82.
188. Alfakih K, Lawrance RA, Maqbool A et al. The clinical significance of a common, functional, X-linked angiotensin Ⅱ type 2-receptor gene polymorphism (-1332 G/A) in a cohort of 509 families with premature coronary artery disease. Eur Heart J,2005,26:584-9.
189. Warnecke C, Mugrauer P, Surder D et al. Intronic ANG Ⅱ type 2 receptor gene polymorphism 1675 G/A modulates receptor protein expression but not mRNA splicing. Am J Physiol Regul Integr Comp Physiol,2005,289:R1729-35.
190. Strauss MH and Hall AS. Angiotensin receptor blockers may increase risk of myocardial infarction:unraveling the ARB-MI paradox. Circulation,2006,114: 838-54.