肾安提取液对糖尿病肾病小鼠模型的干预作用及其分子机理研究
|
摘要
目的：观察肾安提取液对糖尿病肾病(DN)小鼠肾脏的保护作用,对肾脏MASSON染色、超微结构等组织形态学的影响,对肾脏Ⅳ型胶原(Col-Ⅳ)、血管紧张素Ⅱ(AngⅡ)、血管紧张素Ⅱ1型受体(AT1R)、血管紧张素受体相关蛋白(AGTRAP)、结缔组织生长因子(CTGF)、超氧化物歧化酶(SOD)、丙二醛(MDA)、糖基化终产物(AGEs)、糖基化终产物受体(RAGEs)的影响。方法：腹腔注射链脲佐菌素(STZ)建立小鼠DN模型,模型成功后随机分为6组：正常对照组、DN模型组、厄贝沙坦组、肾安高剂量组、肾安中剂量组、肾安低剂量组,药物干预4周后,检测相对肾重、血糖、24h尿蛋白量、血肌酐等；MASSON染色法观察小鼠肾脏一般组织形态改变及胶原纤维变化,透射电镜观察小鼠肾脏超微病理改变；放射免疫法测定肾脏AngⅡ的含量,Realtime-PCR检测肾皮质AT1R、AGTRAP、CTGF、RAGEs mRNA表达,免疫组化法检测肾皮质Col-Ⅳ、AT1R、AGTRAP、CTGF、RAGEs表达；黄嘌呤氧化酶法测定肾组织SOD活性,硫代巴比妥酸反应法检测肾组织MDA含量；分光光度法检测肾组织AGEs含量。结果：DN组小鼠自主活动明显减少,行动迟缓,偶有颤抖,尿量增加明显,多饮多食明显,体型较正常对照组瘦小,MASSON染色法观察发现正常对照组肾小球、肾小管结构正常,毛细血管清晰,呈网状。模型组小鼠肾小球肥大、纤维化明显。透射电镜下观察,糖尿病肾病模型鼠肾脏肾小球基底膜增厚,同一肾小球内不同部位基底膜厚薄差异明显,足细胞肿胀,部分足突融合、甚至消失,部分足突肥大。模型小鼠相对肾重、血糖、24 h尿蛋白蛋量、血肌酐、肾组织AngⅡ、MDA、AGEs、肾皮质CTGF、RAGEs、Col-Ⅳ表达等显著升高(P<0.05或P<0.01),肾组织SOD活性、肾皮质AT1R、AGTRAP表达显著降低(P<0.01)。各药物干预对DN模型小鼠肾脏有保护作用,肾安提取液各个治疗组、厄贝沙坦组有多饮多食现象,尿量增多不明显,活动正常。MASSON染色法观察,EB组、SAG组肾小球、肾小管结构基本正常,内部间隙存在但不规则,呈轻度球囊扩张状。SAZ组、SAD组肾小球肥大,毛细血管网结构塌陷,球囊扩张明显。药物干预组肾皮质CTGF、RAGEs、Col-Ⅳ表达降低(P<0.05或P<0.01),肾皮质AT1R受体、AGTRAP表达升高(P<0.05或P<0.01),肾组织SOD活性增加(P<0.05或P<0.01), AngⅡ、MDA含量降低(P<0.01),DN小鼠蛋白尿、肾功能得到改善。结论：肾安提取液能保护DN小鼠肾脏,其机制可能与降低DN模型小鼠肾组织AngⅡ、MDA、AGEs含量,抑制肾皮质CTGF、RAGEs、Col-Ⅳ表达,增加肾皮质AT1受体、AGTRAP表达,提高肾组织SOD活性有关。
Objective:To investigate the protective effect of Shen'an Extraction on diabetic nephropathy mouse's kidney and effect on renal morphous. And the effect on renal Col-Ⅳ、AngⅡ、AT1R、AGTRAP、CTGF、SOD、MDA、AGEs、RAGEs. Method:The diabetic nephropathy mouse models were induced by intraperitoneal injection of streptozotocin(STZ). The mouse were randomly divided into 6 groups: normal control group; diabetic nephropathy model group; Irbesartan group; high-dose of Shenan group; middle-dose of Shenan group; low-dose of Shenan group. Drug intervention term was 4 weeks. The renal pathological morphous was observed by Masson staining and transmission electron microscope. Relative kidney weight, blood glucose level, serum creatinine content, excretion of the 24 hour urine protein were measured. Renal AngⅡcontent was measured by radioimmunity. The expression of AT1R、AGTRAP、CTGF、RAGE mRNA in renal cortex was detected by Realtime-PCR. The expression of AT1R、AGTRAP、CTGF、RAGE in renal cortex was measured by immunohistochemistry. SOD activity of nephridial tissue was measured by xanthine oxidase method. MDA content of nephridial tissue was measured by thiobarbituric acid reactive substance assay. AGEs content of nephridial tissue was measured by absorption spectrometry.
Result:Autonomic activities of diabetic nephropathy mouse reduced notably. Urinary volume of diabetic nephropathy mouse obviously increased.diabetic nephropathy mouse' glomcrulus got hypertrophia and fibrous degeneration. When observed by transmission electron microscope the glomerular basement membrane of diabetic nephropathy mouse became thick, the podocytes swelled, part of foot process coalesced or overgrow. Relative kidney weight, blood glucose level, serum creatinine、excretion of the 24 hour urine protein, AngⅡMDA、AGEs content and expression of CTGF、RAGEs、Col-Ⅳin cortex renis increased obviously (P<0.05 or P<0.01). SOD activity in nephridial tissue. and expression of AT1R、AGTRAP in cortex renis decreased notably (P<0.01). After Intervention of drugs AngⅡ、MDA、AGEs content and expression of CTGF、RAGEs、Col-Ⅳin cortex renis decreased obviously (P<0.05 or P<0.01).. SOD activity in nephridial tissue.and expression of AT1R、AGTRAP in cortex renis increased markly (P<0.05 or P<0.01). Conclusion: Shen'an Extraction could protect kidney of diabetic nephropathy mouse. The mechanism was related to its inhibiting effect on CTGF、RAGEs、Col-Ⅳexpression in renal cortex and decreasing the AngⅡ、MDA、AGEs content in nephridial tissue and promoting effect on AT1R、AGTRAP expression and elevating the SOD activity in nephridial tissue of diabetic nephropathy mouse.
Subject words Diabetic nephropathy/TCM therapy; Diabetic nephropathy/empirical study; Shen'an Extraction; Renin-angiotensin system; Oxidative stress;Advanced glycosylation end prodrcts
Objective:To investigate the protective effect of Shen'an Extraction on diabetic nephropathy mouse's kidney and effect on renal morphous. And the effect on renal Col-Ⅳ、AngⅡ、AT1R、AGTRAP、CTGF、SOD、MDA、AGEs、RAGEs. Method:The diabetic nephropathy mouse models were induced by intraperitoneal injection of streptozotocin(STZ). The mouse were randomly divided into 6 groups: normal control group; diabetic nephropathy model group; Irbesartan group; high-dose of Shenan group; middle-dose of Shenan group; low-dose of Shenan group. Drug intervention term was 4 weeks. The renal pathological morphous was observed by Masson staining and transmission electron microscope. Relative kidney weight, blood glucose level, serum creatinine content, excretion of the 24 hour urine protein were measured. Renal AngⅡcontent was measured by radioimmunity. The expression of AT1R、AGTRAP、CTGF、RAGE mRNA in renal cortex was detected by Realtime-PCR. The expression of AT1R、AGTRAP、CTGF、RAGE in renal cortex was measured by immunohistochemistry. SOD activity of nephridial tissue was measured by xanthine oxidase method. MDA content of nephridial tissue was measured by thiobarbituric acid reactive substance assay. AGEs content of nephridial tissue was measured by absorption spectrometry.
Result:Autonomic activities of diabetic nephropathy mouse reduced notably. Urinary volume of diabetic nephropathy mouse obviously increased.diabetic nephropathy mouse' glomcrulus got hypertrophia and fibrous degeneration. When observed by transmission electron microscope the glomerular basement membrane of diabetic nephropathy mouse became thick, the podocytes swelled, part of foot process coalesced or overgrow. Relative kidney weight, blood glucose level, serum creatinine、excretion of the 24 hour urine protein, AngⅡMDA、AGEs content and expression of CTGF、RAGEs、Col-Ⅳin cortex renis increased obviously (P<0.05 or P<0.01). SOD activity in nephridial tissue. and expression of AT1R、AGTRAP in cortex renis decreased notably (P<0.01). After Intervention of drugs AngⅡ、MDA、AGEs content and expression of CTGF、RAGEs、Col-Ⅳin cortex renis decreased obviously (P<0.05 or P<0.01).. SOD activity in nephridial tissue.and expression of AT1R、AGTRAP in cortex renis increased markly (P<0.05 or P<0.01). Conclusion: Shen'an Extraction could protect kidney of diabetic nephropathy mouse. The mechanism was related to its inhibiting effect on CTGF、RAGEs、Col-Ⅳexpression in renal cortex and decreasing the AngⅡ、MDA、AGEs content in nephridial tissue and promoting effect on AT1R、AGTRAP expression and elevating the SOD activity in nephridial tissue of diabetic nephropathy mouse.
Subject words Diabetic nephropathy/TCM therapy; Diabetic nephropathy/empirical study; Shen'an Extraction; Renin-angiotensin system; Oxidative stress;Advanced glycosylation end prodrcts
引文
[1]National Kidney Foundation. Kidney Disease Outcome Quality Initiative. K/DOQI clinical practice guidelines for chronic kidneydisease:evaluation, classification, andst ratification[J]. AmJ Kidney Dis,2002,39(2 Suppl 2):S1-246
[2]杨政,白云凯。Ⅰ,Ⅳ型胶原和肾脏疾病.国外医学·泌尿系统分册,2005,25(5)：78.
[3]Umezolo T, Toyoda M, Kato M, et al. Glomerular expression of CTGF,TGF-beta 1 and type IV collagen in diabetic nephropathy[J].J Nephrol,2006,19(6):751.
[4]王露,王平,李永培.血清Ⅳ型胶原和层粘连蛋白在2型糖尿病肾病中的临床价值.中华核医学杂志,2004,24(1)：42-43
[5]周淑红,倪安民,郭倩.2型糖尿病肾病患者尿Ⅳ型胶原检测的临床意义.中国糖尿病杂志,2003,11(5)：374-376
[6]刘志红,李颖健,章精,等。转化生长因子及大黄酸对肾小球系膜细胞葡萄糖转运蛋白功能的影响。中华医学杂志, 1999,79(10)：780
[7]洪小平,张欣洲,贺晓蕾,等。黄芪对糖尿病小鼠肾脏基因表达谱的影响。中国中药杂志,2008,33(6)：676-80
[8]郑虎占。中药现代研究与应用：第五卷[M]。北京：学苑出版社,1997：4225-48
[1]黄锋先,唐盛,杨琼琼,等.2型糖尿病合并肾脏损害的病理与临床分析.中华肾脏病杂志,2005,21：677-680.
[2]王全胜,张晓丽,王玉梅,等.血清和糖皮质激素诱导的蛋白激酶在糖尿病肾病小鼠中的表达及意义. 中华肾脏病杂志,2004,20：442-445.
[3]姜华军,刘建社,朱忠华,等.坎地沙坦对糖尿病肾病小鼠血清和糖皮质激素诱导的蛋白激酶1表达的影响及意义. 中国 药理学通报,2006,22：547-551.
[4]姜华军,刘建社，朱忠华,等.SGK1在糖尿病小鼠肾脏皮质中时间差异性表达及意义. 中国病理生理杂志,2007,23：2278-80.
[5]范萍,杨霓芝.通脉口服液对实验性糖尿病肾病模型大鼠肾脏病理及转化生长因子β-1的影响.广州中医药大学学报,2008,25：514-518.
[6]郑士荣,张景红,朱宇清,等.地灵丹对大鼠糖尿病肾病影响的实验研究.上海中医药杂志,2006,40：62-64.
[7]王月华,郭登洲,王彦凯,等. 活血化瘀消癞通络中药对糖尿病肾病的干预作用. 中国中西医结合肾病杂志,2009,10：345-347.
[8]赵贤俊,李才,南征,等.解毒通络保肾胶囊保护糖尿病大鼠肾脏及影响结缔组织生长因子mRNA的表达效应.中国临床康复,2006,10：174-178,F0003.
[1]Wehbi GJ, Wehbi, Joseph Zimpelmann. Early streptozotocin-diabetes mellitus downregulatesrat kidney AT2 receptors. Am J Physiol Renal Physiol, 2001,280:254-65.
[2]Siragy HM. AT1 and AT2 receptor in the kidney:role in health and disease. Semin Nephrol,2004,24(2):93-100.
[3]Laurent Daviet, Jukka Y. A. Lehtonen, Kouichi Tamura. Cloning and Characterization of ATRAP, a Novel Protein That Interacts with the Angiotensin Ⅱ Type 1 Receptor. J Biol Chem,1999,274 (24):17058-62.
[4]李琳琳,卢衡,郑祥雄.雷帕霉素对糖尿病肾病大鼠病理结构及结缔组织生长因子表达的影响. 中国老年学杂志,2009,29：1909-1912.
[5]Steckelings UM, Rompe F, Kaschina E, Unger T. The evolving story of the RAAS in hypertension, diabetes and CV disease:moving from macrovascular to microvascular targets. Fundam Clin Pharmacol,2009,23(6):693-703.
[6]Koitka A, Tikellis C. Advances in the renin-angiotensin-aldosterone system:relevance to diabetic nephropathy. ScientificWorldJournal,2008,20 (8):434-45.
[7]Balakumar P, Arora MK, Reddy J. Pathophysiology of diabetic nephropathy:involvement of multifaceted signalling mechanism. J Cardiovasc Pharmacol, 2009,54(2):129-38.
[8]Sego S. Pathophysiology of diabetic nephropathy. Nephrol Nurs J,2007,34 (6):631-3.
[9]Wolf G, Ziyadeh FN. Cellular and molecular mechanisms of proteinuria in diabetic nephropathy. Nephron Physiol, 2007,106(2):26-31.
[10]Wolf G, Chen S, Ziyadeh FN. From the periphery of the glomerular capillary wall toward the center of disease: podocyte injury comes of age in diabetic nephropathy. Diabetes,2005,54(6):1626-34.
[11]Maric C. Vasoactive hormones and the diabetic kidney. ScientificWorldJournal,2008,20 (8):470-85.
[12]Sharma R, Sharma M, Reddy S. Chronically increased intrarenal angiotensin Ⅱ causes nephropathy in an animal model of type 2 diabetes. Front Biosci,2006,1 (11):968-76.
[13]Ha H, Lee HB. Reactive oxygen species amplify glucose signalling in renal cells cultured under high glucose and in diabetic kidney. Nephrology,2005,10:S7-10.
[14]Matavelli LC, Huang J, Siragy HM. (Pro)renin Receptor Contributes to Diabetic Nephropathy Through Enhancing Renal Inflammation. Clin Exp Pharmacol Physiol, 2009,Sep 21:Epub ahead of print.
[15]Ogawa S, Kobori H, Ohashi N. Angiotensin Ⅱ Type 1 Receptor Blockers Reduce Urinary Angiotensinogen Excretion and the Levels of Urinary Markers of Oxidative Stress and Inflammation in Patients with Type 2 Diabetic Nephropathy. Biomark Insights,2009,23 (4):97-102.
[16]Kim SK, Jung KH, Lee BC. Protective effect of Tanshinone ⅡA on the early stage of experimental diabetic nephropathy. Biol Pharm Bull,2009,32 (2):220-4.
[17]Liu BC, Sun J, Chen Q. Role of connective tissue growth factor in mediating hypertrophy of human proximal tubular cells induced by angiotensin Ⅱ. Am J Nephrol, 2003,23 (6):429-37.
[18]Kang YS, Park YG, Kim BK. Angiotensin Ⅱ stimulates the synthesis of vascular endothelial growth factor through the p38 mitogen activated protein kinase pathway in cultured mouse podocytes. J Mol Endocrinol, 2006,36(2):377-88.
[19]Matavelli LC, Huang J, Siragy HM. (Pro)renin Receptor Contributes to Diabetic Nephropathy Through Enhancing Renal Inflammation. Clin Exp Pharmacol Physiol, 2009,Sep 21:[Epub ahead of print].
[20]Ha H, Lee HB. Reactive oxygen species amplify glucose signalling in renal cells cultured under high glucose and in diabetic kidney. Nephrology (Carlton),2005,10 Supp:S7-10.
[21]Davis B, Dei Cas A, Long DA. Podocyte-specific expression of angiopoietin-2 causes proteinuria and apoptosis of glomerular endothelia. J Am Soc Nephrol, 2007,18(8):2320-9.
[22]Jaimes EA, Hua P, Tian RX. Human glomerular endothelium: interplay among glucose, free fatty acids, angiotensin Ⅱ, and oxidative stress. Am J Physiol Renal Physiol, 2010,298(1):125-32.
[23]R u ster C, Bondeva T, Franke S. Angiotensin Ⅱ upregulates RAGE expression on podocytes:role of AT2 receptors. Am J Nephrol,2009,29(6):538-50.
[24]Harrison-Bernard LM, Navar LG, Ho MM, Vinson GP. Immunohistochemical localization of ANG Ⅱ AT1 receptor in adult rat kidney using a monoclonal antibody. Am J Physiol. Jul;273 (1 Pt 2):F170-7, 1997,273(1 Pt 2):F170-7.
[25]Wehbi GJ, Zimpelmann J, Carey RM. Early streptozotocin-diabetes mellitus downregulates rat kidney AT2 receptors. Am J Physiol Renal Physiol, 2001,280 (2):F254-65.
[26]Ahmad J, Siddiqui MA, Ahmad H. ffective postponement of diabetic nephropathy with enalapril in normotensive type 2 diabetic patients with microalbuminuria. Diabetes Care,1997,20 (10):1576-81.
[27]谌贻璞.合理应用血管紧张素转换酶抑制剂和血管紧张素AT1受体拮抗剂治疗糖尿病肾病. 中国糖尿病杂志,2003,11(5)：309.
[28]赵林双,廖玉华,向光大,等.缬沙坦治疗抗血管紧张素Ⅱ1型受体自身抗体阳性的高血压合并糖尿病肾病的疗效. 中华高血压杂志,2007,15：469-472.
[29]Lopez-Ilasaca M, Liu X, Tamura K. The angiotensin Ⅱ type I receptor-associated protein, ATRAP, is a transmembrane protein and a modulator of angiotensin Ⅱ signaling. Mol Biol Cell,2003,14 (12):5038-50.
[30]Laurent Daviet, Jukka Y.A. Lehtonen, Kouichi Tamura. Cloning and Characterization of ATRAP, a Novel Protein That Interacts with the Angiotensin Ⅱ Type 1 Receptor. J Biol Chem,199,274 (24):17058-62.
[31]Cui T, Nakagami H, Iwai M. ATRAP, novel AT1 receptor associated protein, enhances internalization of AT1 receptor and inhibits vascular smooth muscle cell growth. Biochem Biophys Res Commun, 2000,279(3):938-41.
[32]Akira Oshita,Masaru Iwai, Rui Chen. Attenuation of Inflammatory Vascular Remodeling by Angiotensin Ⅱ Type 1 Receptor-Associated Protein. Hypertension, 2006:48:671.
[33]Bradham DM, Igarashi A, Potter RL. Connective tissue growth factor:a cysteine-rich mitogen secreted by human vascular endothelial cells is related to the SRC-induced immediate early gene product CEF-10. J Cell Biol,1991,114(6):1285-94.
[34]McLennan SV, Wang XY, Moreno V. Connective tissue growth factor mediates high glucose effects on matrix degradation through tissue inhibitor of matrix metalloproteinase type 1:implications for diabetic nephropathy. Endocrinology,2004,145(12):5646-55.
[35]Kobayashi T, Inoue T, Okada H. Connective tissue growth factor mediates the profibrotic effects of transforming growth factor-beta produced by tubular epithelial cells in response to high glucose. Clin Exp Nephrol,2005,9 (2):114-21.
[36]Ito Y, Aten J, Bende RJ. Expression of connective tissue growth factor in human renal fibrosis. Kidney Int, 1998,53 (4):853-61.
[37]Riser BL, Denichilo M, Cortes P. Regulation of connective tissue growth factor activity in cultured rat mesangial cells and its expression in experimental diabetic glomerulosclerosis. J Am Soc Nephrol, 2000,11(1):25-38.
[38]Wahab NA, Yevdokimobva N, Weston BS. Role of connective tissue growth factor in the pathogenesis of diabetic nephropathy. Biochem J,2001,359 (1):77-87.
[39]Makino H, Mukoyama M, Sugawara A. Roles of connective tissue growth factor and prostanoids in early streptozotocin-induced diabetic rat kidney:the effect of aspirin treatment. Clin Exp Nephrol, 2003,7(1):33-44.
[40]RiBer BL, cortes P. Connective tissue growth factor and its regulation:a new element in diabetic glomerulosclerosis. Ren Fail,2001,23 (3):459-465.
[41]Wahab NA, Yevdokimova N, Weston B. Role of connective tissue growth factor in the pathogenesis of diabetic nephropathy. J Biol chem,2001,359 (1):77-87.
[42]Qi W, Twigg S, Chen X. Integrated actions of transforming growth factor-betal and connective tissue growth factor in renal fibrosis. Am J Physiol Renal Physiol,2005,288 (4):800-9.
[43]刘必成,孙静,刘宏,等.结缔组织生长因子在血管紧张素Ⅱ 诱导的人近端肾小管上皮细胞肥大中的作用. 中华医学杂志,2004,84：1470-1474.
[44]陈珑,刘必成,马坤岭,等.结缔组织生长因子反义寡核苷酸抑制血管紧张素Ⅱ诱导人近曲肾小管上皮细胞肥大米. 肾脏病与透析肾移植杂志,2005,14：318-322.
[45]刘必成,孙静,陈珑,等.结缔组织生长因子介导血管紧张素Ⅱ诱导的人肾近端小管细胞肥大机制. 中华肾脏病杂志,2004,20：190-193.
[46]雷作熹,罗仁,赵晓山,等.小四五颗粒对糖尿病大鼠肾脏肾素—血管紧张素系统的影响. 广州中医药大学学报,2005,22：389-392.
[47]郭登洲,王月华,边东,等.活血化瘀消癥通络中药对糖尿病肾病大鼠肾组织血管紧张素转化酶相关羧肽酶表达的影响.中国全科医学,2008,11：752-754.
[1]曹娜娜,蒋玲.糖尿病慢性并发症发病机制研究进展. 山东医药,2008,48：102-103.
[2]Calabrese V, Mancuso C, Sapienza M. Oxidative stress and cellular stress response in diabetic nephropathy. Cell Stress Chaperones,2007,12 (4):299-306.
[3]牟忠卿,陈丽,傅艺凌,等.糖尿病大鼠肾脏组织中氧化应激的实验研究.中国老年学杂志,2005,25：303-305.
[4]Onozato ML, Tojo A, Goto A, Fujita T. Oxidative stress and nitric oxide synthase in rat diabetic nephropathy: effects of ACEI and ARB. Kidney Int,2002,61(1):186-94.
[5]毛睿睿,薛耀明,周琳.2型糖尿病微量白蛋白尿与氧化应激的关系.山东医药,2009,49：16-18.
[6]钟久昌,余细勇,于汇民,等.血管紧张素转换酶2基因转染对人血管内皮细胞中氧化应激水平的影响. 中华高血压杂志,2008,16：499-502.
[7]刘慰华,黄河清,邓艳辉,等.黄连素对糖尿病肾损伤大鼠肾功能、氧化应激、肾脏醛糖还原酶的影响. 中国药理学通报,2008,24：955-959.
[8]方芳,吴永贵,董婧,等. 白芍总苷对糖尿病大鼠肾组织氧化应激的影响. 中国药理学与毒理学杂志,2008,22：199-204.
[9]刘莹,王淑秋,康玉明,等.灵芝孢子对2型糖尿病大鼠模型肾脏线粒体氧自由基损伤的保护作用. 中国老年学杂志,2008,28：634-636.
[10]何兰杰,刘萍.枸杞多糖对糖尿病大鼠肾脏氧化应激的影响. 中国医院药学杂志,2006,26：1475-1478.
[1]Lagranha CJ, Fiorino P, Casarini DE. Molecular bases of diabetic nephropathy. Arq Bras Endocrinol Metabol. Aug,2007,51 (6):901-12.
[2]Danilczyk U, Penninger JM. Angiotensin-converting enzyme Ⅱ in the heart and the kidney. Circ Res. Mar 3,2006,98 (4):463-71.
[3]Yamagishi S, Fukami K, Ueda S. Molecular mechanisms of diabetic nephropathy and its therapeutic intervention. Curr Drug Targets,2007,8(8):952-9.
[4]Kaji Y, Amano S, Usui T. Expression and function of receptors for advanced glycation and products in bovine corneal endothelial cells. Invest Ophthalmol Vis-Sci, 2003,44:512-28.
[5]周桂华李才苗春生.糖基化终产物对大鼠肾脏结缔组织生长因子的作用. 中华肾脏病杂志,2004,20：159-162.
[6]周桂华,李才,苗春生.糖基化终产物对大鼠肾系膜细胞结缔组织生长因子作用的研究. 中国病理生理杂志,2005,21(2)：256-259.
[7]Ramasamy R, Yan SF, Schmidt AM. RAGE:therapeutic target and biomarker of the inflammatory response-the evidence mounts. J Leukoc Bio.l,2009,86 (3):505-12.
[8]Kalea AZ, Schmidt AM,, Hudson BI. RAGE:a novel biological and genetic marker for vascular disease. Clin Sci, 2009,116 (8):621-37.
[9]Nienhuis HL, Westra J, Smit AJ. AGE and their receptor RAGE in systemic autoimmune diseases:an inflammation propagating factor contributing to accelerated atherosclerosis. Autoimmunity,2009,42(4):302-4.
[10]Sparvero LJ, Asafu-Adjei D, Kang R. RAGE (Receptor for Advanced Glycation Endproducts), RAGE ligands, and their role in cancer and inflammation. J Transl Med, 2009,17 (7):17.
[11]Walcher D, Marx N. Advanced glycation end products and C-peptide-modulators in diabetic vasculopathy and atherogenesis. Semin Immunopathol,2009,31(1):103-11.
[12]Wendt TM, tanji N, Guo J. RAGE drives the development of glomerulosclerosis and implicates podocyte activation in the pathogenesis of diabetic nephropathy. Am J Pathology,2003,162 (4):1123-36.
[13]Heidland A, Sebekova K, Schinzel R. Advanced glycation end products and the progressive course of renal disease. Am J Kidney Dis,2001,38:100-6.
[14]Yamagishi S, Sakurai S, Takasawa S. Development and prevention of advanced diabeticnephropathy in RAGE-overexpressing mice. J Clin Invest, 2001,108 (2):261-8.
[15]Oldfield MD, Bach LA, Forbes JM. AGEs cause epithelial-myofibroblast transdifferentiation via the receptor for advanced glycation end products (RAGE). J Clin Invest,2001,108:1853-63.
[16]Flyvbjerg A, Denner L, Schrijvers BF. Long-term renal effects of a neutralizing RAGE antibody in obese type 2 diabetic mice. Diabetes,2004,53(1):166-72.
[17]龙海波,钟娟,朱艳,等. 肾康丸对早期糖尿病肾病大鼠肾脏晚期糖基化终产物及其受体表达的影响. 中国病理生理杂志,2008,24：1570-1574.
[18]孙桂菊,张勇,黄杰,等.枸杞多糖对Ⅱ型糖尿病大鼠肾脏保护作用及其机制研究.营养学报,2006,28：47-50.
[19]刘志红,李颖健,章精.转化生长因子及大黄酸对肾小球系膜细胞葡萄糖转运蛋白功能的影响. 中华医学杂志,1999,79(10)：780.
[20]洪小平,张欣洲,贺晓蕾.黄芪对糖尿病小鼠肾脏基因表达谱的影响.中国中药杂志,2008,33(6)：676-80.
[21]郑虎占. 中药现代研究与应用：[M]. 北京：学苑出版社,1997.4225-48.
[1]Carlos A, Leon, Leopoldo Raij. Interaction of haemodynamic and metabolic pathways in the genesis of diabetic nephropathy. Journal of Hypertension, 2005,23(11):1931-37.
[2]Lesley Wassef, Robyn G. Langham. Vasoactive Renal Factors and the Progression of Diabetic Nephropathy. Current Pharmaceutical Design,2004,10 (27):3373-84.
[3]刘楠楠,何立群.糖肾宁对糖尿病肾病大鼠血浆ET、CGRP含量的影响. 中国医药指南,2009,7：5-7.
[4]苏宁,李丰,陈津岩,等.黄芩苷对糖尿病肾病大鼠血浆及肾 组织Ang Ⅱ的影响. 中药新药与临床药理,2009,20：201-203.
[5]杨敏,张丽芬,赵进喜,等.黄芪卫矛合剂对糖尿病肾病大鼠肾组织 NO和ET含量影响. 实用中医内科杂志,2006,20：600-601.
[6]吴深涛,黄怀鹏,武娜杰,等. 肾消颗粒对早期糖尿病肾病大鼠肾脏保护作用的实验研究. 中国中医药科技,2006,13：299-300,302.
[7]赵萍,曾燕静,孔瑞芳,等.活血化瘀法治疗早期糖尿病肾病的彩色多谱勒观察. 中华实用中西医杂志,2005,18：1762-1763.
[8]佘宁兰,程弓,王平.杏丁注射液治疗糖尿病肾病临床分析.中国中医药现代远程教育,2008：-.
[9]曾健英,罗正茂,张建林.川芎嗪治疗糖尿病肾病68例.广东医学,2005,26：1004-1005.
[10]Steckelings UM, Rompe F, Kaschina E, Unger T. The evolving story of the RAAS in hypertension, diabetes and CV disease:moving from macrovascular to microvascular targets. Fundam Clin Pharmacol, 2009,23 (6):693-703.
[11]Koitka A, Tikellis C. Advances in the renin-angiotensin-aldosterone system:relevance to diabetic nephropathy. ScientificWorldJournal,2008,20 (8):434-45.
[12]Balakumar P, Arora MK, Reddy J. Pathophysiology of diabetic nephropathy:involvement of multifaceted signalling mechanism. J Cardiovasc Pharmacol, 2009,54(2):129-38.
[13]Sego S. Pathophysiology of diabetic nephropathy. Nephrol Nurs J,2007,34(6):631-3.
[14]雷作熹,罗仁,赵晓山,等.小四五颗粒对糖尿病大鼠肾脏肾素—血管紧张素系统的影响. 广州中医药大学学报,2005,22：389-392.
[15]郭登洲,王月华,边东,等.活血化瘀消癥通络中药对糖尿病肾病大鼠肾组织血管紧张素转化酶相关羧肽酶表达的影响.中国全科医学,2008,11：752-754.
[16]陈津岩,苏宁,陈芝喜.黄芩苷对糖尿病肾病大鼠血管紧张素的抑制作用.甘肃中医,2009,22：66-68.
[17]黄平,金李君,钱康.绞股蓝颗粒对糖尿病肾病大鼠肾脏血管紧张素及内皮素表达的影响. 中国中西医结合肾病杂志,2009：765-768.
[18]姜德友,李秀源,柳成刚,等. 肾消康对糖尿病大鼠肾损伤的保护作用及对血管紧张素Ⅱ影响的实验研究. 四川中医,2006,24：20-21.
[19]Kaji Y, Amano S, Usui T. Expression and function of receptors for advanced glycation and products in bovine corneal endothelial cells. Invest Ophthalmol Vis Sci, 2003,44:512-28.
[20]周桂华,李才,苗春生.糖基化终产物对大鼠肾脏结缔组织生长因子的作用. 中华肾脏病杂志,2004,20(3)：159-162.
[21]周桂华,李才,苗春生.糖基化终产物对大鼠肾系膜细胞结缔组织生长因子作用的研究. 中国病理生理杂志,2005,21(2)：256-259.
[22]Vedantham V, Lalitha P, Velpandian T, et al. Vitreous and aqueous penetration of orally administered moxifloxacin in humans. Eye,2005.
[23]Kalea AZ, Schmidt AM, Hudson BI. RAGE:a novel biological and genetic marker for vascular disease. Clin Sci,2009,116(8):621-37.
[24]Nienhuis HL, Westra J, Smit AJ. AGE and their receptor RAGE in systemic autoimmune diseases:an inflammation propagating factor contributing to accelerated atherosclerosis. Autoimmunity,2009,42(4):302-4.
[25]Sparvero LJ, Asafu-Adjei D, Kang R. RAGE (Receptor for Advanced Glycation Endproducts), RAGE ligands, and their role in cancer and inflammation. J Transl Med, 2009,17 (7):17.
[26]Walcher D, Marx N. Advanced glycation end products and C-peptide-modulators in diabetic vasculopathy and atherogenesis. Semin Immunopathol,2009,31(1):103-11.
[27]Wendt TM, tanji N, Guo J. RAGE drives the development of glomerulosclerosis and implicates podocyte activation in the pathogenesis of diabetic nephropathy. Am J Pathology,2003,162(4):1123-36.
[28]Heidland A, Sebekova K, Schinzel R. Advanced glycation end products and the progressive course of renal disease. Am J Kidney Dis,2001,38:100-6.
[29]Yamagishi S, Sakurai S, Takasawa S. Development and prevention of advanced diabeticnephropathy in RAGE-overexpressing mice. J Clin Invest, 2001,108 (2):261-8.
[30]Oldfield MD, Bach LA, Forbes JM. AGEs cause epithelial-myofibroblast transdifferentiation via the receptor for advanced glycation end products(RAGE). J Clin Invest,2001,108:1853-63.
[31]Flyvbjerg A, Denner L, Schrijvers BF. Long-term renal effects of a neutralizing RAGE antibody in obese type 2 diabetic mice. Diabetes,2004,53(1):166-72.
[32]龙海波,钟娟,朱艳,等. 肾康丸对早期糖尿病肾病大鼠肾脏晚期糖基化终产物及其受体表达的影响. 中国病理生理杂志,2008,24：1570-1574.
[33]孙桂菊,张勇,黄杰,等.枸杞多糖对Ⅱ型糖尿病大鼠肾脏保护作用及其机制研究.营养学报,2006,28：47-50.
[34]李彩蓉,蔡飞,赵辛元,等.茶黄素对糖尿病大鼠肾小球系膜细胞p38丝裂原活化蛋白激酶及细胞外基质合成的影响.茶叶科学,2009,29：470-474.
[35]陈雪功,周雪梅,张琼玉,等.冬梅饮对糖尿病大鼠肾组织非酶糖基化终产物形成的抑制作用. 中医药学刊,2006,24：2222-2223.
[36]Calabrese V, Mancuso C, Sapienza M. Oxidative stress and cellular stress response in diabetic nephropathy. Cell Stress Chaperones,2007,12(4):299-306.
[37]牟忠卿,陈丽,傅艺凌,等.糖尿病大鼠肾脏组织中氧化应激的实验研究.中国老年学杂志,2005,25：303-305.
[38]Onozato ML, Tojo A, Goto A, Fujita T. Oxidative stress and nitric oxide synthase in rat diabetic nephropathy: effects of ACEI and ARB. Kidney Int,2002,61(1):186-94.
[39]毛睿睿,薛耀明,周琳.2型糖尿病微量白蛋白尿与氧化应激的关系. 山东医药,2009,49：16-18.
[40]钟久昌,余细勇,于汇民,等.血管紧张素转换酶2基因转染对人血管内皮细胞中氧化应激水平的影响. 中华高血压杂 志,2008,16：499-502.
[41]刘慰华,黄河清,邓艳辉,等.黄连素对糖尿病肾损伤大鼠肾功能、氧化应激、肾脏醛糖还原酶的影响. 中国药理学通报,2008,24：955-959.
[42]方芳,吴永贵,董婧,等. 白芍总苷对糖尿病大鼠肾组织氧化应激的影响. 中国药理学与毒理学杂志,2008,22：199-204.
[43]高国丽,车光升,董瑶,等. 益肾活血汤对糖尿病大鼠肾功能保护作用的实验研究.中华中医药学刊,2008,26：993-995.
[44]刘莹,王淑秋,康玉明,等.灵芝孢子对2型糖尿病大鼠模型肾脏线粒体氧自由基损伤的保护作用. 中国老年学杂志,2008,28：634-636.
[45]何美霞,黄淑妍,钟艺,等.益肾汤对糖尿病肾病大鼠肾脏氧化应激的影响.中医研究,2008,21：12-14.
[46]何兰杰,刘萍.枸杞多糖对糖尿病大鼠肾脏氧化应激的影响.中国医院药学杂志,2006,26：1475-1478.
[47]毛春谱,李小毅,张红梅,等.银杏叶提取物对早期糖尿病肾病患者氧化应激的影响. 山东医药,2009,49：13-15.
[48]谢辉,汪华林,黄霖,等.降糖保肾方对早期糖尿病大鼠肾脏氧化应激与超微结构的影响. 中国中医急症,2006,15：1133-1135.
[2]杨政,白云凯。Ⅰ,Ⅳ型胶原和肾脏疾病.国外医学·泌尿系统分册,2005,25(5)：78.
[3]Umezolo T, Toyoda M, Kato M, et al. Glomerular expression of CTGF,TGF-beta 1 and type IV collagen in diabetic nephropathy[J].J Nephrol,2006,19(6):751.
[4]王露,王平,李永培.血清Ⅳ型胶原和层粘连蛋白在2型糖尿病肾病中的临床价值.中华核医学杂志,2004,24(1)：42-43
[5]周淑红,倪安民,郭倩.2型糖尿病肾病患者尿Ⅳ型胶原检测的临床意义.中国糖尿病杂志,2003,11(5)：374-376
[6]刘志红,李颖健,章精,等。转化生长因子及大黄酸对肾小球系膜细胞葡萄糖转运蛋白功能的影响。中华医学杂志, 1999,79(10)：780
[7]洪小平,张欣洲,贺晓蕾,等。黄芪对糖尿病小鼠肾脏基因表达谱的影响。中国中药杂志,2008,33(6)：676-80
[8]郑虎占。中药现代研究与应用：第五卷[M]。北京：学苑出版社,1997：4225-48
[1]黄锋先,唐盛,杨琼琼,等.2型糖尿病合并肾脏损害的病理与临床分析.中华肾脏病杂志,2005,21：677-680.
[2]王全胜,张晓丽,王玉梅,等.血清和糖皮质激素诱导的蛋白激酶在糖尿病肾病小鼠中的表达及意义. 中华肾脏病杂志,2004,20：442-445.
[3]姜华军,刘建社,朱忠华,等.坎地沙坦对糖尿病肾病小鼠血清和糖皮质激素诱导的蛋白激酶1表达的影响及意义. 中国 药理学通报,2006,22：547-551.
[4]姜华军,刘建社，朱忠华,等.SGK1在糖尿病小鼠肾脏皮质中时间差异性表达及意义. 中国病理生理杂志,2007,23：2278-80.
[5]范萍,杨霓芝.通脉口服液对实验性糖尿病肾病模型大鼠肾脏病理及转化生长因子β-1的影响.广州中医药大学学报,2008,25：514-518.
[6]郑士荣,张景红,朱宇清,等.地灵丹对大鼠糖尿病肾病影响的实验研究.上海中医药杂志,2006,40：62-64.
[7]王月华,郭登洲,王彦凯,等. 活血化瘀消癞通络中药对糖尿病肾病的干预作用. 中国中西医结合肾病杂志,2009,10：345-347.
[8]赵贤俊,李才,南征,等.解毒通络保肾胶囊保护糖尿病大鼠肾脏及影响结缔组织生长因子mRNA的表达效应.中国临床康复,2006,10：174-178,F0003.
[1]Wehbi GJ, Wehbi, Joseph Zimpelmann. Early streptozotocin-diabetes mellitus downregulatesrat kidney AT2 receptors. Am J Physiol Renal Physiol, 2001,280:254-65.
[2]Siragy HM. AT1 and AT2 receptor in the kidney:role in health and disease. Semin Nephrol,2004,24(2):93-100.
[3]Laurent Daviet, Jukka Y. A. Lehtonen, Kouichi Tamura. Cloning and Characterization of ATRAP, a Novel Protein That Interacts with the Angiotensin Ⅱ Type 1 Receptor. J Biol Chem,1999,274 (24):17058-62.
[4]李琳琳,卢衡,郑祥雄.雷帕霉素对糖尿病肾病大鼠病理结构及结缔组织生长因子表达的影响. 中国老年学杂志,2009,29：1909-1912.
[5]Steckelings UM, Rompe F, Kaschina E, Unger T. The evolving story of the RAAS in hypertension, diabetes and CV disease:moving from macrovascular to microvascular targets. Fundam Clin Pharmacol,2009,23(6):693-703.
[6]Koitka A, Tikellis C. Advances in the renin-angiotensin-aldosterone system:relevance to diabetic nephropathy. ScientificWorldJournal,2008,20 (8):434-45.
[7]Balakumar P, Arora MK, Reddy J. Pathophysiology of diabetic nephropathy:involvement of multifaceted signalling mechanism. J Cardiovasc Pharmacol, 2009,54(2):129-38.
[8]Sego S. Pathophysiology of diabetic nephropathy. Nephrol Nurs J,2007,34 (6):631-3.
[9]Wolf G, Ziyadeh FN. Cellular and molecular mechanisms of proteinuria in diabetic nephropathy. Nephron Physiol, 2007,106(2):26-31.
[10]Wolf G, Chen S, Ziyadeh FN. From the periphery of the glomerular capillary wall toward the center of disease: podocyte injury comes of age in diabetic nephropathy. Diabetes,2005,54(6):1626-34.
[11]Maric C. Vasoactive hormones and the diabetic kidney. ScientificWorldJournal,2008,20 (8):470-85.
[12]Sharma R, Sharma M, Reddy S. Chronically increased intrarenal angiotensin Ⅱ causes nephropathy in an animal model of type 2 diabetes. Front Biosci,2006,1 (11):968-76.
[13]Ha H, Lee HB. Reactive oxygen species amplify glucose signalling in renal cells cultured under high glucose and in diabetic kidney. Nephrology,2005,10:S7-10.
[14]Matavelli LC, Huang J, Siragy HM. (Pro)renin Receptor Contributes to Diabetic Nephropathy Through Enhancing Renal Inflammation. Clin Exp Pharmacol Physiol, 2009,Sep 21:Epub ahead of print.
[15]Ogawa S, Kobori H, Ohashi N. Angiotensin Ⅱ Type 1 Receptor Blockers Reduce Urinary Angiotensinogen Excretion and the Levels of Urinary Markers of Oxidative Stress and Inflammation in Patients with Type 2 Diabetic Nephropathy. Biomark Insights,2009,23 (4):97-102.
[16]Kim SK, Jung KH, Lee BC. Protective effect of Tanshinone ⅡA on the early stage of experimental diabetic nephropathy. Biol Pharm Bull,2009,32 (2):220-4.
[17]Liu BC, Sun J, Chen Q. Role of connective tissue growth factor in mediating hypertrophy of human proximal tubular cells induced by angiotensin Ⅱ. Am J Nephrol, 2003,23 (6):429-37.
[18]Kang YS, Park YG, Kim BK. Angiotensin Ⅱ stimulates the synthesis of vascular endothelial growth factor through the p38 mitogen activated protein kinase pathway in cultured mouse podocytes. J Mol Endocrinol, 2006,36(2):377-88.
[19]Matavelli LC, Huang J, Siragy HM. (Pro)renin Receptor Contributes to Diabetic Nephropathy Through Enhancing Renal Inflammation. Clin Exp Pharmacol Physiol, 2009,Sep 21:[Epub ahead of print].
[20]Ha H, Lee HB. Reactive oxygen species amplify glucose signalling in renal cells cultured under high glucose and in diabetic kidney. Nephrology (Carlton),2005,10 Supp:S7-10.
[21]Davis B, Dei Cas A, Long DA. Podocyte-specific expression of angiopoietin-2 causes proteinuria and apoptosis of glomerular endothelia. J Am Soc Nephrol, 2007,18(8):2320-9.
[22]Jaimes EA, Hua P, Tian RX. Human glomerular endothelium: interplay among glucose, free fatty acids, angiotensin Ⅱ, and oxidative stress. Am J Physiol Renal Physiol, 2010,298(1):125-32.
[23]R u ster C, Bondeva T, Franke S. Angiotensin Ⅱ upregulates RAGE expression on podocytes:role of AT2 receptors. Am J Nephrol,2009,29(6):538-50.
[24]Harrison-Bernard LM, Navar LG, Ho MM, Vinson GP. Immunohistochemical localization of ANG Ⅱ AT1 receptor in adult rat kidney using a monoclonal antibody. Am J Physiol. Jul;273 (1 Pt 2):F170-7, 1997,273(1 Pt 2):F170-7.
[25]Wehbi GJ, Zimpelmann J, Carey RM. Early streptozotocin-diabetes mellitus downregulates rat kidney AT2 receptors. Am J Physiol Renal Physiol, 2001,280 (2):F254-65.
[26]Ahmad J, Siddiqui MA, Ahmad H. ffective postponement of diabetic nephropathy with enalapril in normotensive type 2 diabetic patients with microalbuminuria. Diabetes Care,1997,20 (10):1576-81.
[27]谌贻璞.合理应用血管紧张素转换酶抑制剂和血管紧张素AT1受体拮抗剂治疗糖尿病肾病. 中国糖尿病杂志,2003,11(5)：309.
[28]赵林双,廖玉华,向光大,等.缬沙坦治疗抗血管紧张素Ⅱ1型受体自身抗体阳性的高血压合并糖尿病肾病的疗效. 中华高血压杂志,2007,15：469-472.
[29]Lopez-Ilasaca M, Liu X, Tamura K. The angiotensin Ⅱ type I receptor-associated protein, ATRAP, is a transmembrane protein and a modulator of angiotensin Ⅱ signaling. Mol Biol Cell,2003,14 (12):5038-50.
[30]Laurent Daviet, Jukka Y.A. Lehtonen, Kouichi Tamura. Cloning and Characterization of ATRAP, a Novel Protein That Interacts with the Angiotensin Ⅱ Type 1 Receptor. J Biol Chem,199,274 (24):17058-62.
[31]Cui T, Nakagami H, Iwai M. ATRAP, novel AT1 receptor associated protein, enhances internalization of AT1 receptor and inhibits vascular smooth muscle cell growth. Biochem Biophys Res Commun, 2000,279(3):938-41.
[32]Akira Oshita,Masaru Iwai, Rui Chen. Attenuation of Inflammatory Vascular Remodeling by Angiotensin Ⅱ Type 1 Receptor-Associated Protein. Hypertension, 2006:48:671.
[33]Bradham DM, Igarashi A, Potter RL. Connective tissue growth factor:a cysteine-rich mitogen secreted by human vascular endothelial cells is related to the SRC-induced immediate early gene product CEF-10. J Cell Biol,1991,114(6):1285-94.
[34]McLennan SV, Wang XY, Moreno V. Connective tissue growth factor mediates high glucose effects on matrix degradation through tissue inhibitor of matrix metalloproteinase type 1:implications for diabetic nephropathy. Endocrinology,2004,145(12):5646-55.
[35]Kobayashi T, Inoue T, Okada H. Connective tissue growth factor mediates the profibrotic effects of transforming growth factor-beta produced by tubular epithelial cells in response to high glucose. Clin Exp Nephrol,2005,9 (2):114-21.
[36]Ito Y, Aten J, Bende RJ. Expression of connective tissue growth factor in human renal fibrosis. Kidney Int, 1998,53 (4):853-61.
[37]Riser BL, Denichilo M, Cortes P. Regulation of connective tissue growth factor activity in cultured rat mesangial cells and its expression in experimental diabetic glomerulosclerosis. J Am Soc Nephrol, 2000,11(1):25-38.
[38]Wahab NA, Yevdokimobva N, Weston BS. Role of connective tissue growth factor in the pathogenesis of diabetic nephropathy. Biochem J,2001,359 (1):77-87.
[39]Makino H, Mukoyama M, Sugawara A. Roles of connective tissue growth factor and prostanoids in early streptozotocin-induced diabetic rat kidney:the effect of aspirin treatment. Clin Exp Nephrol, 2003,7(1):33-44.
[40]RiBer BL, cortes P. Connective tissue growth factor and its regulation:a new element in diabetic glomerulosclerosis. Ren Fail,2001,23 (3):459-465.
[41]Wahab NA, Yevdokimova N, Weston B. Role of connective tissue growth factor in the pathogenesis of diabetic nephropathy. J Biol chem,2001,359 (1):77-87.
[42]Qi W, Twigg S, Chen X. Integrated actions of transforming growth factor-betal and connective tissue growth factor in renal fibrosis. Am J Physiol Renal Physiol,2005,288 (4):800-9.
[43]刘必成,孙静,刘宏,等.结缔组织生长因子在血管紧张素Ⅱ 诱导的人近端肾小管上皮细胞肥大中的作用. 中华医学杂志,2004,84：1470-1474.
[44]陈珑,刘必成,马坤岭,等.结缔组织生长因子反义寡核苷酸抑制血管紧张素Ⅱ诱导人近曲肾小管上皮细胞肥大米. 肾脏病与透析肾移植杂志,2005,14：318-322.
[45]刘必成,孙静,陈珑,等.结缔组织生长因子介导血管紧张素Ⅱ诱导的人肾近端小管细胞肥大机制. 中华肾脏病杂志,2004,20：190-193.
[46]雷作熹,罗仁,赵晓山,等.小四五颗粒对糖尿病大鼠肾脏肾素—血管紧张素系统的影响. 广州中医药大学学报,2005,22：389-392.
[47]郭登洲,王月华,边东,等.活血化瘀消癥通络中药对糖尿病肾病大鼠肾组织血管紧张素转化酶相关羧肽酶表达的影响.中国全科医学,2008,11：752-754.
[1]曹娜娜,蒋玲.糖尿病慢性并发症发病机制研究进展. 山东医药,2008,48：102-103.
[2]Calabrese V, Mancuso C, Sapienza M. Oxidative stress and cellular stress response in diabetic nephropathy. Cell Stress Chaperones,2007,12 (4):299-306.
[3]牟忠卿,陈丽,傅艺凌,等.糖尿病大鼠肾脏组织中氧化应激的实验研究.中国老年学杂志,2005,25：303-305.
[4]Onozato ML, Tojo A, Goto A, Fujita T. Oxidative stress and nitric oxide synthase in rat diabetic nephropathy: effects of ACEI and ARB. Kidney Int,2002,61(1):186-94.
[5]毛睿睿,薛耀明,周琳.2型糖尿病微量白蛋白尿与氧化应激的关系.山东医药,2009,49：16-18.
[6]钟久昌,余细勇,于汇民,等.血管紧张素转换酶2基因转染对人血管内皮细胞中氧化应激水平的影响. 中华高血压杂志,2008,16：499-502.
[7]刘慰华,黄河清,邓艳辉,等.黄连素对糖尿病肾损伤大鼠肾功能、氧化应激、肾脏醛糖还原酶的影响. 中国药理学通报,2008,24：955-959.
[8]方芳,吴永贵,董婧,等. 白芍总苷对糖尿病大鼠肾组织氧化应激的影响. 中国药理学与毒理学杂志,2008,22：199-204.
[9]刘莹,王淑秋,康玉明,等.灵芝孢子对2型糖尿病大鼠模型肾脏线粒体氧自由基损伤的保护作用. 中国老年学杂志,2008,28：634-636.
[10]何兰杰,刘萍.枸杞多糖对糖尿病大鼠肾脏氧化应激的影响. 中国医院药学杂志,2006,26：1475-1478.
[1]Lagranha CJ, Fiorino P, Casarini DE. Molecular bases of diabetic nephropathy. Arq Bras Endocrinol Metabol. Aug,2007,51 (6):901-12.
[2]Danilczyk U, Penninger JM. Angiotensin-converting enzyme Ⅱ in the heart and the kidney. Circ Res. Mar 3,2006,98 (4):463-71.
[3]Yamagishi S, Fukami K, Ueda S. Molecular mechanisms of diabetic nephropathy and its therapeutic intervention. Curr Drug Targets,2007,8(8):952-9.
[4]Kaji Y, Amano S, Usui T. Expression and function of receptors for advanced glycation and products in bovine corneal endothelial cells. Invest Ophthalmol Vis-Sci, 2003,44:512-28.
[5]周桂华李才苗春生.糖基化终产物对大鼠肾脏结缔组织生长因子的作用. 中华肾脏病杂志,2004,20：159-162.
[6]周桂华,李才,苗春生.糖基化终产物对大鼠肾系膜细胞结缔组织生长因子作用的研究. 中国病理生理杂志,2005,21(2)：256-259.
[7]Ramasamy R, Yan SF, Schmidt AM. RAGE:therapeutic target and biomarker of the inflammatory response-the evidence mounts. J Leukoc Bio.l,2009,86 (3):505-12.
[8]Kalea AZ, Schmidt AM,, Hudson BI. RAGE:a novel biological and genetic marker for vascular disease. Clin Sci, 2009,116 (8):621-37.
[9]Nienhuis HL, Westra J, Smit AJ. AGE and their receptor RAGE in systemic autoimmune diseases:an inflammation propagating factor contributing to accelerated atherosclerosis. Autoimmunity,2009,42(4):302-4.
[10]Sparvero LJ, Asafu-Adjei D, Kang R. RAGE (Receptor for Advanced Glycation Endproducts), RAGE ligands, and their role in cancer and inflammation. J Transl Med, 2009,17 (7):17.
[11]Walcher D, Marx N. Advanced glycation end products and C-peptide-modulators in diabetic vasculopathy and atherogenesis. Semin Immunopathol,2009,31(1):103-11.
[12]Wendt TM, tanji N, Guo J. RAGE drives the development of glomerulosclerosis and implicates podocyte activation in the pathogenesis of diabetic nephropathy. Am J Pathology,2003,162 (4):1123-36.
[13]Heidland A, Sebekova K, Schinzel R. Advanced glycation end products and the progressive course of renal disease. Am J Kidney Dis,2001,38:100-6.
[14]Yamagishi S, Sakurai S, Takasawa S. Development and prevention of advanced diabeticnephropathy in RAGE-overexpressing mice. J Clin Invest, 2001,108 (2):261-8.
[15]Oldfield MD, Bach LA, Forbes JM. AGEs cause epithelial-myofibroblast transdifferentiation via the receptor for advanced glycation end products (RAGE). J Clin Invest,2001,108:1853-63.
[16]Flyvbjerg A, Denner L, Schrijvers BF. Long-term renal effects of a neutralizing RAGE antibody in obese type 2 diabetic mice. Diabetes,2004,53(1):166-72.
[17]龙海波,钟娟,朱艳,等. 肾康丸对早期糖尿病肾病大鼠肾脏晚期糖基化终产物及其受体表达的影响. 中国病理生理杂志,2008,24：1570-1574.
[18]孙桂菊,张勇,黄杰,等.枸杞多糖对Ⅱ型糖尿病大鼠肾脏保护作用及其机制研究.营养学报,2006,28：47-50.
[19]刘志红,李颖健,章精.转化生长因子及大黄酸对肾小球系膜细胞葡萄糖转运蛋白功能的影响. 中华医学杂志,1999,79(10)：780.
[20]洪小平,张欣洲,贺晓蕾.黄芪对糖尿病小鼠肾脏基因表达谱的影响.中国中药杂志,2008,33(6)：676-80.
[21]郑虎占. 中药现代研究与应用：[M]. 北京：学苑出版社,1997.4225-48.
[1]Carlos A, Leon, Leopoldo Raij. Interaction of haemodynamic and metabolic pathways in the genesis of diabetic nephropathy. Journal of Hypertension, 2005,23(11):1931-37.
[2]Lesley Wassef, Robyn G. Langham. Vasoactive Renal Factors and the Progression of Diabetic Nephropathy. Current Pharmaceutical Design,2004,10 (27):3373-84.
[3]刘楠楠,何立群.糖肾宁对糖尿病肾病大鼠血浆ET、CGRP含量的影响. 中国医药指南,2009,7：5-7.
[4]苏宁,李丰,陈津岩,等.黄芩苷对糖尿病肾病大鼠血浆及肾 组织Ang Ⅱ的影响. 中药新药与临床药理,2009,20：201-203.
[5]杨敏,张丽芬,赵进喜,等.黄芪卫矛合剂对糖尿病肾病大鼠肾组织 NO和ET含量影响. 实用中医内科杂志,2006,20：600-601.
[6]吴深涛,黄怀鹏,武娜杰,等. 肾消颗粒对早期糖尿病肾病大鼠肾脏保护作用的实验研究. 中国中医药科技,2006,13：299-300,302.
[7]赵萍,曾燕静,孔瑞芳,等.活血化瘀法治疗早期糖尿病肾病的彩色多谱勒观察. 中华实用中西医杂志,2005,18：1762-1763.
[8]佘宁兰,程弓,王平.杏丁注射液治疗糖尿病肾病临床分析.中国中医药现代远程教育,2008：-.
[9]曾健英,罗正茂,张建林.川芎嗪治疗糖尿病肾病68例.广东医学,2005,26：1004-1005.
[10]Steckelings UM, Rompe F, Kaschina E, Unger T. The evolving story of the RAAS in hypertension, diabetes and CV disease:moving from macrovascular to microvascular targets. Fundam Clin Pharmacol, 2009,23 (6):693-703.
[11]Koitka A, Tikellis C. Advances in the renin-angiotensin-aldosterone system:relevance to diabetic nephropathy. ScientificWorldJournal,2008,20 (8):434-45.
[12]Balakumar P, Arora MK, Reddy J. Pathophysiology of diabetic nephropathy:involvement of multifaceted signalling mechanism. J Cardiovasc Pharmacol, 2009,54(2):129-38.
[13]Sego S. Pathophysiology of diabetic nephropathy. Nephrol Nurs J,2007,34(6):631-3.
[14]雷作熹,罗仁,赵晓山,等.小四五颗粒对糖尿病大鼠肾脏肾素—血管紧张素系统的影响. 广州中医药大学学报,2005,22：389-392.
[15]郭登洲,王月华,边东,等.活血化瘀消癥通络中药对糖尿病肾病大鼠肾组织血管紧张素转化酶相关羧肽酶表达的影响.中国全科医学,2008,11：752-754.
[16]陈津岩,苏宁,陈芝喜.黄芩苷对糖尿病肾病大鼠血管紧张素的抑制作用.甘肃中医,2009,22：66-68.
[17]黄平,金李君,钱康.绞股蓝颗粒对糖尿病肾病大鼠肾脏血管紧张素及内皮素表达的影响. 中国中西医结合肾病杂志,2009：765-768.
[18]姜德友,李秀源,柳成刚,等. 肾消康对糖尿病大鼠肾损伤的保护作用及对血管紧张素Ⅱ影响的实验研究. 四川中医,2006,24：20-21.
[19]Kaji Y, Amano S, Usui T. Expression and function of receptors for advanced glycation and products in bovine corneal endothelial cells. Invest Ophthalmol Vis Sci, 2003,44:512-28.
[20]周桂华,李才,苗春生.糖基化终产物对大鼠肾脏结缔组织生长因子的作用. 中华肾脏病杂志,2004,20(3)：159-162.
[21]周桂华,李才,苗春生.糖基化终产物对大鼠肾系膜细胞结缔组织生长因子作用的研究. 中国病理生理杂志,2005,21(2)：256-259.
[22]Vedantham V, Lalitha P, Velpandian T, et al. Vitreous and aqueous penetration of orally administered moxifloxacin in humans. Eye,2005.
[23]Kalea AZ, Schmidt AM, Hudson BI. RAGE:a novel biological and genetic marker for vascular disease. Clin Sci,2009,116(8):621-37.
[24]Nienhuis HL, Westra J, Smit AJ. AGE and their receptor RAGE in systemic autoimmune diseases:an inflammation propagating factor contributing to accelerated atherosclerosis. Autoimmunity,2009,42(4):302-4.
[25]Sparvero LJ, Asafu-Adjei D, Kang R. RAGE (Receptor for Advanced Glycation Endproducts), RAGE ligands, and their role in cancer and inflammation. J Transl Med, 2009,17 (7):17.
[26]Walcher D, Marx N. Advanced glycation end products and C-peptide-modulators in diabetic vasculopathy and atherogenesis. Semin Immunopathol,2009,31(1):103-11.
[27]Wendt TM, tanji N, Guo J. RAGE drives the development of glomerulosclerosis and implicates podocyte activation in the pathogenesis of diabetic nephropathy. Am J Pathology,2003,162(4):1123-36.
[28]Heidland A, Sebekova K, Schinzel R. Advanced glycation end products and the progressive course of renal disease. Am J Kidney Dis,2001,38:100-6.
[29]Yamagishi S, Sakurai S, Takasawa S. Development and prevention of advanced diabeticnephropathy in RAGE-overexpressing mice. J Clin Invest, 2001,108 (2):261-8.
[30]Oldfield MD, Bach LA, Forbes JM. AGEs cause epithelial-myofibroblast transdifferentiation via the receptor for advanced glycation end products(RAGE). J Clin Invest,2001,108:1853-63.
[31]Flyvbjerg A, Denner L, Schrijvers BF. Long-term renal effects of a neutralizing RAGE antibody in obese type 2 diabetic mice. Diabetes,2004,53(1):166-72.
[32]龙海波,钟娟,朱艳,等. 肾康丸对早期糖尿病肾病大鼠肾脏晚期糖基化终产物及其受体表达的影响. 中国病理生理杂志,2008,24：1570-1574.
[33]孙桂菊,张勇,黄杰,等.枸杞多糖对Ⅱ型糖尿病大鼠肾脏保护作用及其机制研究.营养学报,2006,28：47-50.
[34]李彩蓉,蔡飞,赵辛元,等.茶黄素对糖尿病大鼠肾小球系膜细胞p38丝裂原活化蛋白激酶及细胞外基质合成的影响.茶叶科学,2009,29：470-474.
[35]陈雪功,周雪梅,张琼玉,等.冬梅饮对糖尿病大鼠肾组织非酶糖基化终产物形成的抑制作用. 中医药学刊,2006,24：2222-2223.
[36]Calabrese V, Mancuso C, Sapienza M. Oxidative stress and cellular stress response in diabetic nephropathy. Cell Stress Chaperones,2007,12(4):299-306.
[37]牟忠卿,陈丽,傅艺凌,等.糖尿病大鼠肾脏组织中氧化应激的实验研究.中国老年学杂志,2005,25：303-305.
[38]Onozato ML, Tojo A, Goto A, Fujita T. Oxidative stress and nitric oxide synthase in rat diabetic nephropathy: effects of ACEI and ARB. Kidney Int,2002,61(1):186-94.
[39]毛睿睿,薛耀明,周琳.2型糖尿病微量白蛋白尿与氧化应激的关系. 山东医药,2009,49：16-18.
[40]钟久昌,余细勇,于汇民,等.血管紧张素转换酶2基因转染对人血管内皮细胞中氧化应激水平的影响. 中华高血压杂 志,2008,16：499-502.
[41]刘慰华,黄河清,邓艳辉,等.黄连素对糖尿病肾损伤大鼠肾功能、氧化应激、肾脏醛糖还原酶的影响. 中国药理学通报,2008,24：955-959.
[42]方芳,吴永贵,董婧,等. 白芍总苷对糖尿病大鼠肾组织氧化应激的影响. 中国药理学与毒理学杂志,2008,22：199-204.
[43]高国丽,车光升,董瑶,等. 益肾活血汤对糖尿病大鼠肾功能保护作用的实验研究.中华中医药学刊,2008,26：993-995.
[44]刘莹,王淑秋,康玉明,等.灵芝孢子对2型糖尿病大鼠模型肾脏线粒体氧自由基损伤的保护作用. 中国老年学杂志,2008,28：634-636.
[45]何美霞,黄淑妍,钟艺,等.益肾汤对糖尿病肾病大鼠肾脏氧化应激的影响.中医研究,2008,21：12-14.
[46]何兰杰,刘萍.枸杞多糖对糖尿病大鼠肾脏氧化应激的影响.中国医院药学杂志,2006,26：1475-1478.
[47]毛春谱,李小毅,张红梅,等.银杏叶提取物对早期糖尿病肾病患者氧化应激的影响. 山东医药,2009,49：13-15.
[48]谢辉,汪华林,黄霖,等.降糖保肾方对早期糖尿病大鼠肾脏氧化应激与超微结构的影响. 中国中医急症,2006,15：1133-1135.