肾络通对梗阻性肾病大鼠炎性介质表达的影响
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摘要
由于先天性或获得性泌尿系梗阻所致的梗阻性肾病是急性或慢性肾功能衰竭的常见原因之一，也是难治性反复发作的尿路感染的常见诱发因素。造成慢性泌尿系梗阻的机制非常复杂，其中包括血液动力学改变、炎性介质、血管活性物质、氧化应激等因素的共同参与，最终导致肾脏损伤及肾功能衰竭。肾脏病的发生与肾素-血管紧张素-醛固酮系统(Renin-angiotensin-aldosterone, RAAS)有密切关系，目前对血管紧张素Ⅱ(angiotensinⅡ, AngⅡ)的研究较多，其通过转化生长因子-β(Transforminggrowth factor-β, TGF-β)途径促进肾间质纤维化(Renal interstitial fibrosis,RIF)的机制已经比较明确，应用血管紧张素转化酶抑制剂(angiotensinconverting enzyme inhibitors, ACEI)及血管紧张素Ⅱ受体阻断剂(angiotensin II receptor blockers, ARB)后可减轻慢性肾脏病患者肾脏结构和功能的损伤，但仍有不少患者，即便足量的ACEI及ARB治疗亦未能有效，说明有其他因素如炎性损伤、氧化应激的参与。已有的研究表明，炎性损伤在慢性疾病持续进展中发挥重要作用，故抗炎治疗对于慢性疾病的预后有重要意义。这种炎性损伤并非单纯由外界感染所致，而是以内源性炎性损伤为主，且与RIF的持续进展密切相关，炎性介质在其中的作用也得以重视。有研究指出炎性介质例如单核细胞趋化蛋白-1(monocytechemotactic protein1, MCP-1)、白介素-1β(Interleukin1β, IL-1β)、肿瘤坏死因子(tumor necrosis factorα, TNF-α)和诱导型一氧化氮合酶(inducednitric oxide synthase，iNOS)是各种慢性肾脏疾病中引起肾脏炎症和纤维化的重要因素。随着对RAAS的深入研究，发现除了AngⅡ外，醛固酮也可通过激活其下游效应介质血清糖皮质激素诱导蛋白激酶1(Serum andglucocorticoid-induced protein kinase1, SGK-1)及核转录因子κB (NuclearfactorκB, NF-κB)、氧化应激等多种途径导致肾脏炎性细胞浸润和细胞外基质(extracellular matrix, ECM)积聚，最终导致RIF的进展，故阻断醛固酮活化造成的炎性损伤对于减缓肾脏病的进展有重要意义。本次实验通过单侧输尿管结扎(unilateral ureteral obstruction, UUO)建立梗阻性肾病间质纤维化实验动物模型，观察盐皮质激素受体阻断剂依普利酮和化瘀涤痰通络方肾络通煎剂对单侧输尿管梗阻大鼠炎性介质表达的影响，利用实时定量荧光聚合酶链式反应(Real-time polymerase Chain Reaction, Real-timePCR)、免疫组化、蛋白质印迹法(Western blot)、酶联免疫吸附法(enzymelinked immunosorbent assay, ELISA)、放射免疫分析法等技术检测血清醛固酮、血清和糖皮质激素诱导蛋白激酶1(Serum and glucocorticoid-inducedprotein kinase1, SGK-1)及MCP-1、TNF-α、iNOS、IL-1β、核转录因子κB (Nuclear factorκB, NF-κB)和α平滑肌激动蛋白(α-smooth muscleprotein, α-SMA)等指标的变化，从组织、分子、基因水平研究肾络通煎剂的作用机制，为中药治疗梗阻性肾病提供理论和实验依据。
第一部分“毒”、“瘀”伤肾机制及关联
简述了“毒”和“瘀”的概念、分类、形成机制、两者在肾病中的发病机制，以及毒邪和瘀血的相互影响、毒瘀互结在肾病中的作用、毒瘀相关的分子生物学基础及临床意义等内容。
大量实验研究表明，肾间质纤维化是各种慢性肾脏疾病的病理表现和共同通路，而炎性损伤在肾间质纤维化的进程中是一种启动和诱发因素。现代医学研究表明，炎性细胞的浸润、炎性介质的释放、促纤维化细胞因子的表达等均可归属于中医“内毒致病”范畴，而细胞外基质在肾脏的积聚是“瘀”的表现，由此可见，以炎性损伤为特征的“毒”为起因，纤维化为表现的“瘀”为结果，二者交互错杂，导致和加重肾间质纤维化，且贯穿于肾脏病的整个病理过程。同时，也总结出“毒”和“瘀”可作为慢性肾脏病的基本病机。
在临床上，肾脏病的进展与感染有密切关系，或因感染而诱发，或因感染而加重，且肾病患者易于感染，这种感染所致的炎性损伤在肾间质纤维化的进展中发挥着重要的作用，抗炎治疗可能是治疗靶点。“毒”、“瘀”病机学说的提出为临床治疗慢性肾脏疾病提供了理论依据，对于慢性肾病的进展可能有重要意义。
第二部分肾络通对梗阻性肾病大鼠肾脏组织病理形态学的影响
方法：48只Wistar大鼠随机分为假手术组(Sham group)、UUO组(UUOgroup)、依普利酮组(EPL group)、肾络通组(SLT group)，每组12只。实验动物自由进食和饮水，温度条件控制在(22±2)℃。适应性饲养1WK后，除假手术组(Sham group)，其余大鼠按照Iwai T的方法制备单侧输尿管梗阻模型。大鼠给以10%水合氯醛注射后，于左侧中腹部切开皮肤，游离左侧输尿管，分别在输尿管上1/3处和中1/3处用丝线结扎，切断输尿管，逐层缝合皮肤。假手术组仅将输尿管游离但不结扎离断。术后第3天肾脏组织病理显示炎性细胞浸润，第5日后肾间质胶原纤维沉积，术后第10天梗阻侧肾脏明显大于对侧，肾间质大量炎性细胞浸润以及胶原纤维沉积，肾小管上皮细胞变性、浊肿、脱落甚至坏死，肾小管部分萎缩，管腔闭塞或扩张，与文献报道相似，符合肾间质纤维化病理改变，模型复制成功。本次实验成功率为92％，UUO术后大鼠死亡5只，用备用大鼠补足。术后开始给药，依普利酮组给以依普利酮100mg/(kg.d)从饲料中加入，肾络通组给以肾络通煎剂26g/(kg.d)入水瓶饮用，假手术组及UUO组给予等容量生理盐水饮用。均每天1次。连续干预10天。观察一般情况。于实验结束时，称重，断头取血，分离血清，用于指标检测；取左侧(梗阻侧)肾脏称重，计算各组肾重/体重比值，进行肾脏组织HE、MASSON染色，观察组织病理学改变。
数据资料结果使用SPSS13.0for windows统计软件分析处理。各组数据比较前先进行正态性及方差齐性检验，满足正态性及方差齐性者，采用方差分析，多组比较采用单因素方差分析(One-wayANOVA)，组间比较采用LSD检验。数值变量以均数加减标准差(x±s)表示。显著性差异水平以0.05和0.01为标准。
结果：
1各组大鼠一般情况比较
实验中大鼠死亡5只，用备用大鼠补足。整个实验过程中假手术组大鼠一般情况良好：每日饮食、饮水量稳定，体重逐步增长，毛发有光泽，活动敏捷，对外界刺激反应灵敏。UUO术后1天，造模动物的进食量、饮水量、体重均有所下降。术后6天，UUO组大鼠整体状态欠佳：活动较前明显减少，毛发松散无光泽。与假手数组相比，造模动物体重不增反而下降。UUO手术10天后，造模大鼠体重增长缓慢，且与假手术组有显著性差异(P<0.01, P<0.05)；与UUO组相比，依普利酮组及肾络通组大鼠梗阻侧肾重，肾重/体重指数明显下降(P<0.01, P<0.05)。UUO手术后，造模大鼠进食量、饮水量、24h尿量均有所下降，但各组之间无明显差异(P>0.05)。
2各组大鼠肾组织病理形态学改变
HE染色显示，假手术组肾脏结构基本正常，肾小管上皮细胞排列整齐，无浊肿，间质无水肿，偶见炎性细胞浸润；UUO组肾间质大量炎性细胞浸润，肾小管明显扩张，上皮细胞变性、浊肿、脱落甚至坏死；依普利酮组及肾络通组小管扩张及上皮细胞水肿坏死与UUO组基本相同，但炎性细胞浸润明显减轻。Masson染色显示，假手术组有少量胶原纤维表达，可见于肾小球/肾小管基底膜及肾间质；UUO组结构紊乱，胶原成分显著增多，以肾间质为主；依普利酮组及肾络通组胶原纤维表达较假手术组增多，但与UUO组相比明显减少。
3各组大鼠肾间质炎性细胞计数比较
与假手术组比较，UUO组大鼠炎性细胞浸润明显增多(P<0.01)。与UUO组相比，依普利酮组、肾络通组大鼠炎性细胞浸润减少有显著性差异(P<0.01, P<0.05)。与髓质区相比，皮质区炎性细胞浸润明显增多有显著性差异(P<0.01, P<0.05)；与皮质区比较，皮髓交界区质区炎性细胞浸润减少，有显著性差异(P<0.01, P<0.05)。
第三部分肾络通对梗阻性肾病大鼠MCP-1、TNF-α、IL-1β、iNOS等炎性介质表达的影响
方法：动物分组、模型复制、给药方法同第二部分，共10天。实验结束时留取血清和肾脏标本，采用ELISA测定血清MCP-1含量，放射免疫法测定血清TNF-α、iNOS、IL-1β含量，Real time-PCR、免疫组化、Western blot检测MCP-1、TNF-αmRNA及蛋白的表达。统计学方法同第二部分。
结果：
1各组大鼠血清MCP-1、TNF-α、iNOS、IL-1β表达比较
与假手术组比较，UUO组中血清MCP-1、TNF-α、iNOS、IL-1β含量明显升高，差异有统计学意义(P<0.01, P<0.05)。与UUO组比较，依普利酮组及肾络通组血清MCP-1、TNF-α、iNOS、IL-1β含量均减少，其中以依普利酮组更为明显，差异有统计学意义(P<0.01, P<0.05)。
2Real-time PCR检测MCP-1mRNA、TNF-αmRNA的表达
与假手术组比较，UUO组中MCP-1mRNA及TNF-αmRNA表达明显增强(P<0.01)。与UUO组比较，依普利酮组及肾络通组MCP-1mRNA及TNF-α mRNA表达均显著下调，其中以依普利酮组更为明显，差异有统计学意义(P<0.01)。
3免疫组化检测MCP-1、TNF-α表达
假手术组MCP-1、TNF-α呈弱表达， UUO组中MCP、TNF-α表达明显增强，主要表达于肾小管上皮细胞胞浆。与UUO组比较，依普利酮及肾络通组其表达范围及强度均显著减弱。
4Western Blot检测MCP-1及TNF-α蛋白表达
与假手术组比较，UUO组MCP-1、TNF-α蛋白表达明显上调。与UUO组比较，依普利酮组及肾络通组其表达均被下调，其中以依普利酮组下调更为明显，差异有统计学意义(P<0.01)。
第四部分肾络通对梗阻性肾病大鼠血清醛固酮及SGK-1表达的影响
方法：动物分组、模型复制、给药方法同第二部分，共10天。实验结束时留取血清和肾脏标本，采用放射免疫分析法检测血清醛固酮含量，Real-time PCR、Western blot测定肾组织SGK-1mRNA及蛋白表达。统计学方法同第二部分。
结果：
1放射免疫法检测各组大鼠血清醛固酮含量
与假手术组比较，UUO组中血清醛固酮含量明显升高，差异有统计学意义(P<0.01)；与UUO组比较，依普利酮组血清醛固酮含量有下降趋势，但无统计学意义(P>0.05)，肾络通组血清醛固酮含量明显降低，有统计学差异(P<0.01)。
2Real-time PCR检测SGK-1mRNA的表达
与假手术组比较，UUO组中SGK-1mRNA表达明显增强。与UUO组比较，依普利酮及肾络通组SGK-1mRNA表达均显著下调。
3Western Blot检测SGK-1蛋白表达
与假手术组比较，UUO组SGK-1蛋白表达明显上调。与UUO组比较，依普利酮组及肾络通组其表达均被下调，其中以依普利酮组下降更为显著。
第五部分肾络通对梗阻性肾病大鼠及α-SMA及NF-κB表达的影响
方法：动物分组、模型复制、给药方法同第二部分，共10天。实验结束时留取肾脏标本，采用免疫组化、Western Blot检测α-SMA及NF-кB蛋白表达。统计学方法同第二部分。
结果：
1免疫组化检测各组大鼠NF-κB、α-SMA表达
假手术组NF-κB呈弱表达，主要表达于肾小管上皮细胞；UUO组NF-κB表达明显增强，近曲小管尤为明显；依普利酮组及肾络通组NF-κB表达范围及强度较UUO组均明显减弱。
假手术组α-SMA仅表达于血管，肾间质及上皮细胞未见表达；UUO组α-SMA表达明显增强，以扩张的肾小管表达为甚，间质亦可见到阳性表达；依普利酮组及肾络通组α-SMA局部呈中度表达，间质可见少量表达。
2Western Blot检测各组大鼠α-SMA、NF-кB表达
与假手术组比较，UUO组α-SMA、NF-кB蛋白表达明显上调，差异有统计学意义(P<0.01)。与UUO组比较，依普利酮组及肾络通组其表达均被下调，其中以依普利酮组下调更为明显，差异有统计学意义(P<0.01)。
结论：
1“毒”和“瘀”是慢性肾病的基本病机，以炎性损伤为特征的“毒”为起因，以纤维化为表现的“瘀”为结果，二者相互关联、相互促进，导致和加重肾间质纤维化，且贯穿于肾脏病的整个病理过程。
2结扎单侧输尿管复制肾间质纤维化实验动物模型，肾间质炎性细胞浸润及胶原成分显著增多。肾络通及依普利酮能显著减轻UUO诱导的肾实质损伤，减少炎性细胞浸润，延缓间质纤维化进展。
3炎性损伤是梗阻性肾病的重要起始因素，炎性介质在其中发挥重要作用。其中，MCP-1、TNF-α、IL-1β及iNOS等炎性介质是慢性肾脏疾病中介导的肾脏炎症和间质纤维化的重要因子。肾络通和依普利酮能下调其表达，从而抑制梗阻性肾病中炎性损伤和炎性细胞浸润，进而延缓间质纤维化的进展。
4醛固酮可通过激活其下游效应介质SGK-1引起肾脏炎性损伤。肾络通和依普利酮能降低血清醛固酮含量，下调SGK-1mRNA和蛋白表达，从而进一步抑制梗阻性肾病炎性损伤和间质纤维化进展。
5肾络通和依普利酮可以通过NF-κB通路，下调炎性介质表达，抑制信号传导，从而抑制细胞的表型转化，减轻肾脏炎性损伤，减缓肾间质纤维化的进展。
Obstructive nephropathy due to congenital or acquired urinary tractobstruction is the first primary cause of acute or chronic renal failure(CRF)and also a major induced cause of urinary tract infection. The mechanism ofchronic urinary tract obstruction is very complicated, including hemodynamicchanges, inflammatory mediators, vascular active substances, oxidative stress,which eventually lead to kidney damage and renal function failure. There is aclosed relationship between renal disease and the system ofRenin-angiotensin-aldosterone (RAAS). At present, the study of angiotensinII(Ang Ⅱ) is more, and the mechanism that AngⅡ through transforminggrowth factor-β (TGF-β) pathway to promote renal interstitial fibrosis (RIF)has more clear. Application of angiotensin converting enzyme inhibitors(ACEI)and/or angiotensin Ⅱ blockers (ARB) caninhibit the damage to structure andfunction of chronic renal disease. But there are still many patients, even ifadministration of plenty of ACEI and ARB are not effective, indicating thereare other factors such as inflammation injury, oxidative stress to participatethis process. Existing studies have shown that inflammatory lesions play animportant role in the progress of chronic disease, therefore anti-inflammatorytherapy has important significance for the prognosis of chronic diseases. Thisinflammatory damage is not caused by infection, but it is endogenous, andclosely related to renal interstitial fibrosis. Moreover, inflammatory mediatorsplay an important role in the process of renal interstitial fibrosis. Studies havepointed out that inflammatory mediators such as monocyte chemotacticprotein1(MCP-1), Interleukin1β(IL-1β), tumor necrosis factor α(TNF-α),induced nitric oxide synthase(iNOS) are important factors of inflammationand fibrosis in chronic renal disease. With the study of RAAS, in addition toAng Ⅱ, aldosterone can also be activated by Serum and glucocorticoid-induced protein kinase1(SGK-1), Nuclear factor κB (NF-κB),oxidative stress and so on, further cause infiltration of renal inflammatorycells and accumulation of extracellular matrix (ECM), eventually leading tothe progress of the RIF. Therefore, blocking activated aldosterone to inhibitinflammatory can delay the progress of chronic renal disease. In our study,renal interstitial fibrosis animal model was established by unilateral ureteralobstruction (UUO), and serum aldosterone, SGK-1, MCP-1, TNF-α, iNOS,IL-1β, NF-κB and α-SMA were detected by Real-time PCR,immunohistochenical method, Western blot. The effect of mineralocorticoidreceptor blocker Eplerenone and Chinese herbs was observed, whether caninhibite the expression of inflammatory mediators by blocking aldosteronesecretion, future inhibite cell phenotype transformation, and providetheoretical and experimental basis.
PartⅠ Mechanism and Relationship of Toxin and Stasis on Renal Injury.
"Toxin" and "Stasis" were briefly introduced with the concept,classification, formation mechanism, the role in the pathogenesis of kidneydisease, and interaction with stasis and toxin, the role of both in kidneydisease, molecular biology and clinical application.
Many experimental study showed that renal interstitial fibrosis waspathological change and common pathway of a variety of chronic kidneydiseases, and inflammatory lesions was a original and induced factor in thisprocess. Modern medical studies have shown that infiltration of inflammatorycells and the expression of inflammatory mediators and inducing fibrosiscytokines were attributable to traditional Chinese medicine “endogenoustoxin”, however the accumulation of extracellular matrix in the kidney was aperformance of “stasis”, therefore “toxin” was the cause characterized byinflammation injury,“stasis” was the result characterized by renal interstitialfibrosis, and these two factors were interrelated and they interacted with eachother, caused and aggravated renal interstitial fibrosis, and run through thewhole pathological process of kidney disease. At the same time, we alsosummed up that “toxin and “stasis” can be used as the basic pathogenesis of chronic kidney disease.
In clinic, there was a closed relationship between the progress of kidneydisease and infection, and kidney diseases were induced or aggravated byinfection, and nephropathy patients proned to infection. Inflammation injurycaused by infection played an important role in the progress of renalinterstitial fibrosis, and anti-inflammatory therapy may be a therapeutic target."Poison","Yu" pathogenesis theory have provided the theory basis for theclinical treatment of chronic kidney disease, and have important significancefor the progress of chronic kidney disease.
PartⅡ Effect of Shenluotong Decoction on pathomorphology in the Ratswith Obstructive Nephropathy
Methods:48Wistar rats were randomly divided into the shamgroup(n=12), UUO group (n=12), EPL group(n=12), SLT group(n=12). Ratswere free to eat and drink, and temperature was controled in the condition(22±2)℃. After adaptive feeding1WK, except the Sham group’rats, the otherrats were established model of unilateral ureteral obstruction according to themethod of Iwai T. After anesthesia with10%chloral hydrate, the rats weresliced through the left middle abdominal skin, separated the left ureter, ligatedrespectively on ureteral1/3and middle1/3ligation with silk, cut off the ureter,then sutured in skin by layer to layer. The rats in Sham group were onlyseparated the left ureter, but not ligated and cutted off the ureter. At3daysafter operation, renal pathology of modeling rats showed a significant increasewith infiltration of inflammatory cells, as well as at5days after operation,pathological changes showed renal collagen deposition, therefore this modelwas successfully copied. The success rate of this surgery was92%, and fiverats were died after UUO operation. Rats were supplemented with alternaterats. After operation, the rats were treated with100mg/kg Eplerenone in EPLgroup and26g/kg in SLT group; others in sham and UUO group administeredwith the same volume of saline once a day. At the10day after surgery, allrats were sacrificed and specimens of blood were got to detect index and leftkidney was cut to be measured the index of kidney weight/body weight(KW/BW). Parts of left kidney were prepared respectively for HE andMASSON staining.
The data were counted by SPSS13.0software. Before comparison of eachgroup, tests of normality and homogeneity of variance were given. If the datacan achieve such criteria, the results were analyzed with One way ANOVA.The data were expressed as mean±SD. All results are considered significantat P<0.05and P<0.01.
Results:
1Index of kidney weight, body weight and kidney weight/body weight
After surgery,5rats were died and rats were supplemented with alternaterats. The general situation of Sham group’s rats were in good condition in thewhole experimental process: daily diet and water were stable, the growth ofweight was gradual, hair was shiny, activity was agile, and response toexternal stimuli was sensitive. At1day after surgery, all rats showed thatwater intake, food intake and weight were down-regulated. At6days aftersurgery, the general situation of UUO group’s rats were not optimal: activitywas decreased significantly, and hair was loose and dull. The weight of UUOmodeling animals were not increased but decreased. At10days after surgery,the weight of modeling animals were increased slowly, and there weresignificant differences compared with Sham group(P<0.01, P<0.05);compared with UUO group, obstructed kidney weight and kidney weight/body weight were also decreased significantly(P<0.01, P<0.05).After UUOoperation, food intake, water intake and urine volume in UUOmodeling ratswere decreased, but there was no significant difference between each group.
2The Result of Pathomorphology
HE staining showed that basic structure of kidney was normal, tubularepithelial cells arranged regularly, interstitial edema was almost nought and ithad few inflammation cells in Sham group. There were a large number ofinflammation cells infiltration, and renal tubular epithelial cells weredenatured, shed and turgid in UUO group. There were some inflammation cellinfiltration and renal tubular epithelial cells were turgid in treatment groups, but it was lighter than UUO group. Masson staining showed that a littlecollagen deposition in glomerular/tubular basement membrane and renalinterstitium in Sham group. The structure were disordered and tubularinterstitial collagen were significantly increased in UUO group. There weresome degree of collagen deposition in treatment groups, but it wassignificantly reduced compared with the UUO group.
3The count of renal interstitial inflammatory cells
Compared with the Sham group, the number of inflammatory cells wasincreased significantly in the UUO group (P<0.01). After treatment, thenumber of inflammatory cells was significantly lower in both EPL group andSLT group (P<0.01, P<0.05). Compared with Medulla area, the number ofinflammatory cells was significantly heighest in cortical area; Compared withcortical area, the number of inflammatory cells was significantly decreased inboundary area (P<0.01, P<0.05).
Part Ⅲ Effect of Shenluotong Decoction on Inflammatory Mediators inthe Rats with Obstructive Nephropathy
Methods: The methods of animal grouping, model establishment,medication and statistics were the same to PartⅡ,10days. The expression ofMCP-1in kidneys were detected by ELISA, and serum content of TNF-α,iNOS and IL-1β were detected by radioimmunoassay. The mRNA and proteinexpression of MCP-1and TNF-α were detected by Real time-PCR,immunohistochemistry and Western Blot respectively.
Results:
1Serum content of inflammatory mediators
Compared of the rats in Sham group, serum content of MCP-1, TNF-α,iNOS and IL-1β were increased significantly (P<0.01, P<0.05). Compared ofthe rats in UUO group, serum content of MCP-1, TNF-α, iNOS and IL-1βwere decreased significantly in both EPL group and SLT group (P<0.01,P<0.05).
2The results of Real time-PCR
Compared with the rats in Sham group, the mRNA expression of MCP-1 and TNF-α were enhanced obviously in UUO group(P<0.01). Compared withthe rats in UUO group, the high expression of MCP-1mRNA and TNF-αmRNA was down-regulated respectively in both EPL and SLT group(P<0.01).
3The results of Immunohistochemistry
The expression of MCP-1and TNF-α were weaker in Sham group, aswell as both were strengthed, and mainly located in renal tubular epithelialcells cytoplasm in UUO group. Compared with the rats in UUO group, theexpression of MCP-1and TNF-α were decreased in range and terror in twotreatment groups.
4The results of Western Blot
Compared with the rats in Sham group, the protein expression of MCP-1and TNF-α were enhanced obviously in UUO group. Compared of the rats inUUO group, the protein expression of MCP-1and TNF-α were decreasedsignificantly in both EPL group and SLT group (P<0.01).
Part Ⅳ Effect of Shenluotong Decoction on Serum aldosterone andSGK-1in the Rats with Obstructive Nephropathy
Methods: The methods of animal grouping, model establishment,medication and statistics were the same to PartⅡ,10days. Serum aldosteronewas detected by radioimmunoassay, and the mRNA and protein expression ofSGK-1were detected by Real-time PCR and Western blot respectively.
Results:
1The results of Radioimmunoassay
Compared of the rats in Sham group, the secretion of serum aldosteronewas increased significantly in UUO group(P<0.01). Compared of the rats inUUO group, the content of serum aldosterone was expressed with a downwardtrend, but this reduction wasn't statistically significant in EPL group(P>0.05).Serum aldosterone was reduced in SLT group significantly (P<0.01).
2The results of Real-time PCR
Compared of the rats in Sham group, the mRNA expression of SGK-1were enhanced obviously in UUO group(P<0.01). Compared with the rats inUUO group, the mRNA expression of SGK-1were down-regulated significantly (P<0.01).
3The results of Western Blot
Compared of the rats in Sham group, the protein expression of SGK-1were enhanced obviously in UUO group(P<0.01). Compared with the rats inUUO group, the protein expression of SGK-1were down-regulatedsignificantly (P<0.01).
Part Ⅴ Effect of Shenluotong Decoction on α-SMA and NF-κB in theRats with Obstructive Nephropathy
Methods: The methods of animal grouping, model establishment,medication and statistics were the same to PartⅡ,10days. The proteinexpression of NF-кB and α-SMA were detected by immunohistochemistry andWestern Blot.
Results:
1The results of Immunohistochemistry
In Sham group, there were weak expression of NF-κ B mainly in renaltubular epithelial cells; Compared of the rats in Sham group, the expression ofNF-κ B significantly increased and obviously in the proximal tubule in UUOgroup.In ELP and SLT groups, the expression of NF-κ B were significantlydecreased in range and strength.
In Sham group, there were a few expressions of α-SMA only in vascularsmooth muscle cells. The expression ofα-SMA were remarkably increased inUUO group than that in corresponding Sham group with the expanding scopeof tubulointerstitium in cortical and corticomedullary area. Compared with therats in UUO group, the expression of α-SMA were reduced obviously in bothEPL group and SLT group.
2The results of Western Blot
Compared of the rats in Sham group, the protein expression of α-SMAand NF-кB were enhanced obviously in UUO group(P<0.01). Compared withthe rats in UUO group, the protein expression of α-SMA and NF-кB weredown-regulated significantly (P<0.01).
Conclusions:
1“toxin” and “stasis” were the basic pathogenesis of chronic kidneydisease.“toxin” was the cause characterized by inflammation injury,“stasis”was the result characterized by renal interstitial fibrosis, and these two factorswere interrelated and they were interacted with each other, caused andaggravated renal interstitial fibrosis, and run through the whole pathologicalprocess of kidney disease.
2The animal models of renal interstitial fibrosis were established byunilateral ureteral obstruction. Inflammatory cells infiltration and Collagentissues in the kidney were increased remarkably in UUO modeling rats.Chinese herbs and eplerenone can prevent kidney damage induced by UUO,reduce inflammatory cells infiltration and delay the progress of interstitialfibrosis.
3Inflammatory is an important original factor of obstructive nephropathy,and inflammatory mediators play an important role in this process.Inflammatory mediators, such as MCP-1, TNF-α, IL-1β and iNOS, areimportant factors in mediating inflammation and interstitial fibrosis of chronickidney disease. Chinese herbs and eplerenone can down-regulate theexpression of MCP-1, TNF-α, IL-1β and iNOS, future inhibit infiltration ofinflammatory cells and inflammatory injury, and delay the progress ofinterstitial fibrosis.
4In addition to the Ang II, aldosterone may also induce renalinflammatory and infiltration of inflammatory cells through activation ofSGK-1. Chinese herbs and eplerenone can reduce the content of serumaldosterone, down-regulate mRNA and protein expression of SGK-1, futureinhibit inflammatory and interstitial fibrosis of Obstructive Nephropathy.
5Chinese herbs and eplerenone can down-regulate the expression ofinflammatory mediators by NF-κB pathway, inhibit signal transduction,thereby inhibit cell phenotype transformation, reduce renal inflammatory, anddelay the progress of renal interstitial fibrosis.
第一部分“毒”、“瘀”伤肾机制及关联
简述了“毒”和“瘀”的概念、分类、形成机制、两者在肾病中的发病机制，以及毒邪和瘀血的相互影响、毒瘀互结在肾病中的作用、毒瘀相关的分子生物学基础及临床意义等内容。
大量实验研究表明，肾间质纤维化是各种慢性肾脏疾病的病理表现和共同通路，而炎性损伤在肾间质纤维化的进程中是一种启动和诱发因素。现代医学研究表明，炎性细胞的浸润、炎性介质的释放、促纤维化细胞因子的表达等均可归属于中医“内毒致病”范畴，而细胞外基质在肾脏的积聚是“瘀”的表现，由此可见，以炎性损伤为特征的“毒”为起因，纤维化为表现的“瘀”为结果，二者交互错杂，导致和加重肾间质纤维化，且贯穿于肾脏病的整个病理过程。同时，也总结出“毒”和“瘀”可作为慢性肾脏病的基本病机。
在临床上，肾脏病的进展与感染有密切关系，或因感染而诱发，或因感染而加重，且肾病患者易于感染，这种感染所致的炎性损伤在肾间质纤维化的进展中发挥着重要的作用，抗炎治疗可能是治疗靶点。“毒”、“瘀”病机学说的提出为临床治疗慢性肾脏疾病提供了理论依据，对于慢性肾病的进展可能有重要意义。
第二部分肾络通对梗阻性肾病大鼠肾脏组织病理形态学的影响
方法：48只Wistar大鼠随机分为假手术组(Sham group)、UUO组(UUOgroup)、依普利酮组(EPL group)、肾络通组(SLT group)，每组12只。实验动物自由进食和饮水，温度条件控制在(22±2)℃。适应性饲养1WK后，除假手术组(Sham group)，其余大鼠按照Iwai T的方法制备单侧输尿管梗阻模型。大鼠给以10%水合氯醛注射后，于左侧中腹部切开皮肤，游离左侧输尿管，分别在输尿管上1/3处和中1/3处用丝线结扎，切断输尿管，逐层缝合皮肤。假手术组仅将输尿管游离但不结扎离断。术后第3天肾脏组织病理显示炎性细胞浸润，第5日后肾间质胶原纤维沉积，术后第10天梗阻侧肾脏明显大于对侧，肾间质大量炎性细胞浸润以及胶原纤维沉积，肾小管上皮细胞变性、浊肿、脱落甚至坏死，肾小管部分萎缩，管腔闭塞或扩张，与文献报道相似，符合肾间质纤维化病理改变，模型复制成功。本次实验成功率为92％，UUO术后大鼠死亡5只，用备用大鼠补足。术后开始给药，依普利酮组给以依普利酮100mg/(kg.d)从饲料中加入，肾络通组给以肾络通煎剂26g/(kg.d)入水瓶饮用，假手术组及UUO组给予等容量生理盐水饮用。均每天1次。连续干预10天。观察一般情况。于实验结束时，称重，断头取血，分离血清，用于指标检测；取左侧(梗阻侧)肾脏称重，计算各组肾重/体重比值，进行肾脏组织HE、MASSON染色，观察组织病理学改变。
数据资料结果使用SPSS13.0for windows统计软件分析处理。各组数据比较前先进行正态性及方差齐性检验，满足正态性及方差齐性者，采用方差分析，多组比较采用单因素方差分析(One-wayANOVA)，组间比较采用LSD检验。数值变量以均数加减标准差(x±s)表示。显著性差异水平以0.05和0.01为标准。
结果：
1各组大鼠一般情况比较
实验中大鼠死亡5只，用备用大鼠补足。整个实验过程中假手术组大鼠一般情况良好：每日饮食、饮水量稳定，体重逐步增长，毛发有光泽，活动敏捷，对外界刺激反应灵敏。UUO术后1天，造模动物的进食量、饮水量、体重均有所下降。术后6天，UUO组大鼠整体状态欠佳：活动较前明显减少，毛发松散无光泽。与假手数组相比，造模动物体重不增反而下降。UUO手术10天后，造模大鼠体重增长缓慢，且与假手术组有显著性差异(P<0.01, P<0.05)；与UUO组相比，依普利酮组及肾络通组大鼠梗阻侧肾重，肾重/体重指数明显下降(P<0.01, P<0.05)。UUO手术后，造模大鼠进食量、饮水量、24h尿量均有所下降，但各组之间无明显差异(P>0.05)。
2各组大鼠肾组织病理形态学改变
HE染色显示，假手术组肾脏结构基本正常，肾小管上皮细胞排列整齐，无浊肿，间质无水肿，偶见炎性细胞浸润；UUO组肾间质大量炎性细胞浸润，肾小管明显扩张，上皮细胞变性、浊肿、脱落甚至坏死；依普利酮组及肾络通组小管扩张及上皮细胞水肿坏死与UUO组基本相同，但炎性细胞浸润明显减轻。Masson染色显示，假手术组有少量胶原纤维表达，可见于肾小球/肾小管基底膜及肾间质；UUO组结构紊乱，胶原成分显著增多，以肾间质为主；依普利酮组及肾络通组胶原纤维表达较假手术组增多，但与UUO组相比明显减少。
3各组大鼠肾间质炎性细胞计数比较
与假手术组比较，UUO组大鼠炎性细胞浸润明显增多(P<0.01)。与UUO组相比，依普利酮组、肾络通组大鼠炎性细胞浸润减少有显著性差异(P<0.01, P<0.05)。与髓质区相比，皮质区炎性细胞浸润明显增多有显著性差异(P<0.01, P<0.05)；与皮质区比较，皮髓交界区质区炎性细胞浸润减少，有显著性差异(P<0.01, P<0.05)。
第三部分肾络通对梗阻性肾病大鼠MCP-1、TNF-α、IL-1β、iNOS等炎性介质表达的影响
方法：动物分组、模型复制、给药方法同第二部分，共10天。实验结束时留取血清和肾脏标本，采用ELISA测定血清MCP-1含量，放射免疫法测定血清TNF-α、iNOS、IL-1β含量，Real time-PCR、免疫组化、Western blot检测MCP-1、TNF-αmRNA及蛋白的表达。统计学方法同第二部分。
结果：
1各组大鼠血清MCP-1、TNF-α、iNOS、IL-1β表达比较
与假手术组比较，UUO组中血清MCP-1、TNF-α、iNOS、IL-1β含量明显升高，差异有统计学意义(P<0.01, P<0.05)。与UUO组比较，依普利酮组及肾络通组血清MCP-1、TNF-α、iNOS、IL-1β含量均减少，其中以依普利酮组更为明显，差异有统计学意义(P<0.01, P<0.05)。
2Real-time PCR检测MCP-1mRNA、TNF-αmRNA的表达
与假手术组比较，UUO组中MCP-1mRNA及TNF-αmRNA表达明显增强(P<0.01)。与UUO组比较，依普利酮组及肾络通组MCP-1mRNA及TNF-α mRNA表达均显著下调，其中以依普利酮组更为明显，差异有统计学意义(P<0.01)。
3免疫组化检测MCP-1、TNF-α表达
假手术组MCP-1、TNF-α呈弱表达， UUO组中MCP、TNF-α表达明显增强，主要表达于肾小管上皮细胞胞浆。与UUO组比较，依普利酮及肾络通组其表达范围及强度均显著减弱。
4Western Blot检测MCP-1及TNF-α蛋白表达
与假手术组比较，UUO组MCP-1、TNF-α蛋白表达明显上调。与UUO组比较，依普利酮组及肾络通组其表达均被下调，其中以依普利酮组下调更为明显，差异有统计学意义(P<0.01)。
第四部分肾络通对梗阻性肾病大鼠血清醛固酮及SGK-1表达的影响
方法：动物分组、模型复制、给药方法同第二部分，共10天。实验结束时留取血清和肾脏标本，采用放射免疫分析法检测血清醛固酮含量，Real-time PCR、Western blot测定肾组织SGK-1mRNA及蛋白表达。统计学方法同第二部分。
结果：
1放射免疫法检测各组大鼠血清醛固酮含量
与假手术组比较，UUO组中血清醛固酮含量明显升高，差异有统计学意义(P<0.01)；与UUO组比较，依普利酮组血清醛固酮含量有下降趋势，但无统计学意义(P>0.05)，肾络通组血清醛固酮含量明显降低，有统计学差异(P<0.01)。
2Real-time PCR检测SGK-1mRNA的表达
与假手术组比较，UUO组中SGK-1mRNA表达明显增强。与UUO组比较，依普利酮及肾络通组SGK-1mRNA表达均显著下调。
3Western Blot检测SGK-1蛋白表达
与假手术组比较，UUO组SGK-1蛋白表达明显上调。与UUO组比较，依普利酮组及肾络通组其表达均被下调，其中以依普利酮组下降更为显著。
第五部分肾络通对梗阻性肾病大鼠及α-SMA及NF-κB表达的影响
方法：动物分组、模型复制、给药方法同第二部分，共10天。实验结束时留取肾脏标本，采用免疫组化、Western Blot检测α-SMA及NF-кB蛋白表达。统计学方法同第二部分。
结果：
1免疫组化检测各组大鼠NF-κB、α-SMA表达
假手术组NF-κB呈弱表达，主要表达于肾小管上皮细胞；UUO组NF-κB表达明显增强，近曲小管尤为明显；依普利酮组及肾络通组NF-κB表达范围及强度较UUO组均明显减弱。
假手术组α-SMA仅表达于血管，肾间质及上皮细胞未见表达；UUO组α-SMA表达明显增强，以扩张的肾小管表达为甚，间质亦可见到阳性表达；依普利酮组及肾络通组α-SMA局部呈中度表达，间质可见少量表达。
2Western Blot检测各组大鼠α-SMA、NF-кB表达
与假手术组比较，UUO组α-SMA、NF-кB蛋白表达明显上调，差异有统计学意义(P<0.01)。与UUO组比较，依普利酮组及肾络通组其表达均被下调，其中以依普利酮组下调更为明显，差异有统计学意义(P<0.01)。
结论：
1“毒”和“瘀”是慢性肾病的基本病机，以炎性损伤为特征的“毒”为起因，以纤维化为表现的“瘀”为结果，二者相互关联、相互促进，导致和加重肾间质纤维化，且贯穿于肾脏病的整个病理过程。
2结扎单侧输尿管复制肾间质纤维化实验动物模型，肾间质炎性细胞浸润及胶原成分显著增多。肾络通及依普利酮能显著减轻UUO诱导的肾实质损伤，减少炎性细胞浸润，延缓间质纤维化进展。
3炎性损伤是梗阻性肾病的重要起始因素，炎性介质在其中发挥重要作用。其中，MCP-1、TNF-α、IL-1β及iNOS等炎性介质是慢性肾脏疾病中介导的肾脏炎症和间质纤维化的重要因子。肾络通和依普利酮能下调其表达，从而抑制梗阻性肾病中炎性损伤和炎性细胞浸润，进而延缓间质纤维化的进展。
4醛固酮可通过激活其下游效应介质SGK-1引起肾脏炎性损伤。肾络通和依普利酮能降低血清醛固酮含量，下调SGK-1mRNA和蛋白表达，从而进一步抑制梗阻性肾病炎性损伤和间质纤维化进展。
5肾络通和依普利酮可以通过NF-κB通路，下调炎性介质表达，抑制信号传导，从而抑制细胞的表型转化，减轻肾脏炎性损伤，减缓肾间质纤维化的进展。
Obstructive nephropathy due to congenital or acquired urinary tractobstruction is the first primary cause of acute or chronic renal failure(CRF)and also a major induced cause of urinary tract infection. The mechanism ofchronic urinary tract obstruction is very complicated, including hemodynamicchanges, inflammatory mediators, vascular active substances, oxidative stress,which eventually lead to kidney damage and renal function failure. There is aclosed relationship between renal disease and the system ofRenin-angiotensin-aldosterone (RAAS). At present, the study of angiotensinII(Ang Ⅱ) is more, and the mechanism that AngⅡ through transforminggrowth factor-β (TGF-β) pathway to promote renal interstitial fibrosis (RIF)has more clear. Application of angiotensin converting enzyme inhibitors(ACEI)and/or angiotensin Ⅱ blockers (ARB) caninhibit the damage to structure andfunction of chronic renal disease. But there are still many patients, even ifadministration of plenty of ACEI and ARB are not effective, indicating thereare other factors such as inflammation injury, oxidative stress to participatethis process. Existing studies have shown that inflammatory lesions play animportant role in the progress of chronic disease, therefore anti-inflammatorytherapy has important significance for the prognosis of chronic diseases. Thisinflammatory damage is not caused by infection, but it is endogenous, andclosely related to renal interstitial fibrosis. Moreover, inflammatory mediatorsplay an important role in the process of renal interstitial fibrosis. Studies havepointed out that inflammatory mediators such as monocyte chemotacticprotein1(MCP-1), Interleukin1β(IL-1β), tumor necrosis factor α(TNF-α),induced nitric oxide synthase(iNOS) are important factors of inflammationand fibrosis in chronic renal disease. With the study of RAAS, in addition toAng Ⅱ, aldosterone can also be activated by Serum and glucocorticoid-induced protein kinase1(SGK-1), Nuclear factor κB (NF-κB),oxidative stress and so on, further cause infiltration of renal inflammatorycells and accumulation of extracellular matrix (ECM), eventually leading tothe progress of the RIF. Therefore, blocking activated aldosterone to inhibitinflammatory can delay the progress of chronic renal disease. In our study,renal interstitial fibrosis animal model was established by unilateral ureteralobstruction (UUO), and serum aldosterone, SGK-1, MCP-1, TNF-α, iNOS,IL-1β, NF-κB and α-SMA were detected by Real-time PCR,immunohistochenical method, Western blot. The effect of mineralocorticoidreceptor blocker Eplerenone and Chinese herbs was observed, whether caninhibite the expression of inflammatory mediators by blocking aldosteronesecretion, future inhibite cell phenotype transformation, and providetheoretical and experimental basis.
PartⅠ Mechanism and Relationship of Toxin and Stasis on Renal Injury.
"Toxin" and "Stasis" were briefly introduced with the concept,classification, formation mechanism, the role in the pathogenesis of kidneydisease, and interaction with stasis and toxin, the role of both in kidneydisease, molecular biology and clinical application.
Many experimental study showed that renal interstitial fibrosis waspathological change and common pathway of a variety of chronic kidneydiseases, and inflammatory lesions was a original and induced factor in thisprocess. Modern medical studies have shown that infiltration of inflammatorycells and the expression of inflammatory mediators and inducing fibrosiscytokines were attributable to traditional Chinese medicine “endogenoustoxin”, however the accumulation of extracellular matrix in the kidney was aperformance of “stasis”, therefore “toxin” was the cause characterized byinflammation injury,“stasis” was the result characterized by renal interstitialfibrosis, and these two factors were interrelated and they interacted with eachother, caused and aggravated renal interstitial fibrosis, and run through thewhole pathological process of kidney disease. At the same time, we alsosummed up that “toxin and “stasis” can be used as the basic pathogenesis of chronic kidney disease.
In clinic, there was a closed relationship between the progress of kidneydisease and infection, and kidney diseases were induced or aggravated byinfection, and nephropathy patients proned to infection. Inflammation injurycaused by infection played an important role in the progress of renalinterstitial fibrosis, and anti-inflammatory therapy may be a therapeutic target."Poison","Yu" pathogenesis theory have provided the theory basis for theclinical treatment of chronic kidney disease, and have important significancefor the progress of chronic kidney disease.
PartⅡ Effect of Shenluotong Decoction on pathomorphology in the Ratswith Obstructive Nephropathy
Methods:48Wistar rats were randomly divided into the shamgroup(n=12), UUO group (n=12), EPL group(n=12), SLT group(n=12). Ratswere free to eat and drink, and temperature was controled in the condition(22±2)℃. After adaptive feeding1WK, except the Sham group’rats, the otherrats were established model of unilateral ureteral obstruction according to themethod of Iwai T. After anesthesia with10%chloral hydrate, the rats weresliced through the left middle abdominal skin, separated the left ureter, ligatedrespectively on ureteral1/3and middle1/3ligation with silk, cut off the ureter,then sutured in skin by layer to layer. The rats in Sham group were onlyseparated the left ureter, but not ligated and cutted off the ureter. At3daysafter operation, renal pathology of modeling rats showed a significant increasewith infiltration of inflammatory cells, as well as at5days after operation,pathological changes showed renal collagen deposition, therefore this modelwas successfully copied. The success rate of this surgery was92%, and fiverats were died after UUO operation. Rats were supplemented with alternaterats. After operation, the rats were treated with100mg/kg Eplerenone in EPLgroup and26g/kg in SLT group; others in sham and UUO group administeredwith the same volume of saline once a day. At the10day after surgery, allrats were sacrificed and specimens of blood were got to detect index and leftkidney was cut to be measured the index of kidney weight/body weight(KW/BW). Parts of left kidney were prepared respectively for HE andMASSON staining.
The data were counted by SPSS13.0software. Before comparison of eachgroup, tests of normality and homogeneity of variance were given. If the datacan achieve such criteria, the results were analyzed with One way ANOVA.The data were expressed as mean±SD. All results are considered significantat P<0.05and P<0.01.
Results:
1Index of kidney weight, body weight and kidney weight/body weight
After surgery,5rats were died and rats were supplemented with alternaterats. The general situation of Sham group’s rats were in good condition in thewhole experimental process: daily diet and water were stable, the growth ofweight was gradual, hair was shiny, activity was agile, and response toexternal stimuli was sensitive. At1day after surgery, all rats showed thatwater intake, food intake and weight were down-regulated. At6days aftersurgery, the general situation of UUO group’s rats were not optimal: activitywas decreased significantly, and hair was loose and dull. The weight of UUOmodeling animals were not increased but decreased. At10days after surgery,the weight of modeling animals were increased slowly, and there weresignificant differences compared with Sham group(P<0.01, P<0.05);compared with UUO group, obstructed kidney weight and kidney weight/body weight were also decreased significantly(P<0.01, P<0.05).After UUOoperation, food intake, water intake and urine volume in UUOmodeling ratswere decreased, but there was no significant difference between each group.
2The Result of Pathomorphology
HE staining showed that basic structure of kidney was normal, tubularepithelial cells arranged regularly, interstitial edema was almost nought and ithad few inflammation cells in Sham group. There were a large number ofinflammation cells infiltration, and renal tubular epithelial cells weredenatured, shed and turgid in UUO group. There were some inflammation cellinfiltration and renal tubular epithelial cells were turgid in treatment groups, but it was lighter than UUO group. Masson staining showed that a littlecollagen deposition in glomerular/tubular basement membrane and renalinterstitium in Sham group. The structure were disordered and tubularinterstitial collagen were significantly increased in UUO group. There weresome degree of collagen deposition in treatment groups, but it wassignificantly reduced compared with the UUO group.
3The count of renal interstitial inflammatory cells
Compared with the Sham group, the number of inflammatory cells wasincreased significantly in the UUO group (P<0.01). After treatment, thenumber of inflammatory cells was significantly lower in both EPL group andSLT group (P<0.01, P<0.05). Compared with Medulla area, the number ofinflammatory cells was significantly heighest in cortical area; Compared withcortical area, the number of inflammatory cells was significantly decreased inboundary area (P<0.01, P<0.05).
Part Ⅲ Effect of Shenluotong Decoction on Inflammatory Mediators inthe Rats with Obstructive Nephropathy
Methods: The methods of animal grouping, model establishment,medication and statistics were the same to PartⅡ,10days. The expression ofMCP-1in kidneys were detected by ELISA, and serum content of TNF-α,iNOS and IL-1β were detected by radioimmunoassay. The mRNA and proteinexpression of MCP-1and TNF-α were detected by Real time-PCR,immunohistochemistry and Western Blot respectively.
Results:
1Serum content of inflammatory mediators
Compared of the rats in Sham group, serum content of MCP-1, TNF-α,iNOS and IL-1β were increased significantly (P<0.01, P<0.05). Compared ofthe rats in UUO group, serum content of MCP-1, TNF-α, iNOS and IL-1βwere decreased significantly in both EPL group and SLT group (P<0.01,P<0.05).
2The results of Real time-PCR
Compared with the rats in Sham group, the mRNA expression of MCP-1 and TNF-α were enhanced obviously in UUO group(P<0.01). Compared withthe rats in UUO group, the high expression of MCP-1mRNA and TNF-αmRNA was down-regulated respectively in both EPL and SLT group(P<0.01).
3The results of Immunohistochemistry
The expression of MCP-1and TNF-α were weaker in Sham group, aswell as both were strengthed, and mainly located in renal tubular epithelialcells cytoplasm in UUO group. Compared with the rats in UUO group, theexpression of MCP-1and TNF-α were decreased in range and terror in twotreatment groups.
4The results of Western Blot
Compared with the rats in Sham group, the protein expression of MCP-1and TNF-α were enhanced obviously in UUO group. Compared of the rats inUUO group, the protein expression of MCP-1and TNF-α were decreasedsignificantly in both EPL group and SLT group (P<0.01).
Part Ⅳ Effect of Shenluotong Decoction on Serum aldosterone andSGK-1in the Rats with Obstructive Nephropathy
Methods: The methods of animal grouping, model establishment,medication and statistics were the same to PartⅡ,10days. Serum aldosteronewas detected by radioimmunoassay, and the mRNA and protein expression ofSGK-1were detected by Real-time PCR and Western blot respectively.
Results:
1The results of Radioimmunoassay
Compared of the rats in Sham group, the secretion of serum aldosteronewas increased significantly in UUO group(P<0.01). Compared of the rats inUUO group, the content of serum aldosterone was expressed with a downwardtrend, but this reduction wasn't statistically significant in EPL group(P>0.05).Serum aldosterone was reduced in SLT group significantly (P<0.01).
2The results of Real-time PCR
Compared of the rats in Sham group, the mRNA expression of SGK-1were enhanced obviously in UUO group(P<0.01). Compared with the rats inUUO group, the mRNA expression of SGK-1were down-regulated significantly (P<0.01).
3The results of Western Blot
Compared of the rats in Sham group, the protein expression of SGK-1were enhanced obviously in UUO group(P<0.01). Compared with the rats inUUO group, the protein expression of SGK-1were down-regulatedsignificantly (P<0.01).
Part Ⅴ Effect of Shenluotong Decoction on α-SMA and NF-κB in theRats with Obstructive Nephropathy
Methods: The methods of animal grouping, model establishment,medication and statistics were the same to PartⅡ,10days. The proteinexpression of NF-кB and α-SMA were detected by immunohistochemistry andWestern Blot.
Results:
1The results of Immunohistochemistry
In Sham group, there were weak expression of NF-κ B mainly in renaltubular epithelial cells; Compared of the rats in Sham group, the expression ofNF-κ B significantly increased and obviously in the proximal tubule in UUOgroup.In ELP and SLT groups, the expression of NF-κ B were significantlydecreased in range and strength.
In Sham group, there were a few expressions of α-SMA only in vascularsmooth muscle cells. The expression ofα-SMA were remarkably increased inUUO group than that in corresponding Sham group with the expanding scopeof tubulointerstitium in cortical and corticomedullary area. Compared with therats in UUO group, the expression of α-SMA were reduced obviously in bothEPL group and SLT group.
2The results of Western Blot
Compared of the rats in Sham group, the protein expression of α-SMAand NF-кB were enhanced obviously in UUO group(P<0.01). Compared withthe rats in UUO group, the protein expression of α-SMA and NF-кB weredown-regulated significantly (P<0.01).
Conclusions:
1“toxin” and “stasis” were the basic pathogenesis of chronic kidneydisease.“toxin” was the cause characterized by inflammation injury,“stasis”was the result characterized by renal interstitial fibrosis, and these two factorswere interrelated and they were interacted with each other, caused andaggravated renal interstitial fibrosis, and run through the whole pathologicalprocess of kidney disease.
2The animal models of renal interstitial fibrosis were established byunilateral ureteral obstruction. Inflammatory cells infiltration and Collagentissues in the kidney were increased remarkably in UUO modeling rats.Chinese herbs and eplerenone can prevent kidney damage induced by UUO,reduce inflammatory cells infiltration and delay the progress of interstitialfibrosis.
3Inflammatory is an important original factor of obstructive nephropathy,and inflammatory mediators play an important role in this process.Inflammatory mediators, such as MCP-1, TNF-α, IL-1β and iNOS, areimportant factors in mediating inflammation and interstitial fibrosis of chronickidney disease. Chinese herbs and eplerenone can down-regulate theexpression of MCP-1, TNF-α, IL-1β and iNOS, future inhibit infiltration ofinflammatory cells and inflammatory injury, and delay the progress ofinterstitial fibrosis.
4In addition to the Ang II, aldosterone may also induce renalinflammatory and infiltration of inflammatory cells through activation ofSGK-1. Chinese herbs and eplerenone can reduce the content of serumaldosterone, down-regulate mRNA and protein expression of SGK-1, futureinhibit inflammatory and interstitial fibrosis of Obstructive Nephropathy.
5Chinese herbs and eplerenone can down-regulate the expression ofinflammatory mediators by NF-κB pathway, inhibit signal transduction,thereby inhibit cell phenotype transformation, reduce renal inflammatory, anddelay the progress of renal interstitial fibrosis.
引文
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