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缬沙坦对单侧输尿管梗阻大鼠肾间质纤维化的影响
周健淞1,陈刚2,沈液渠2,吴美2,何立群2*
0
(1.南通大学第三附属医院肾内科,无锡 214041;2.上海中医药大学附属曙光医院肾内科,上海 201203)
摘要:
目的探讨血管紧张素ⅡⅠ型受体拮抗剂(AT1RA)缬沙坦对单侧输尿管梗阻(UUO)大鼠肾间质纤维化(RIF)的影响及其可能机制。方法35只SD大鼠随机分为假手术组、模型组和缬沙坦组(n=10),建立大鼠UUO模型,于术后4周检测血清肌酐(SCr)、血尿素氮(BUN)、血浆血管紧张素Ⅱ(AngⅡ),尿N-乙酰-β-D-氨基葡萄糖苷酶(NAG)、尿β2-微球蛋白(β2-MG);取梗阻侧肾组织,以H-E、Masson染色观察肾小管间质病变,免疫组织化学染色观察α-平滑肌肌动蛋白(α-SMA)、纤维连接蛋白(FN)、纤溶酶原激活物抑制剂1(PAI-1)、转化生长因子β1(TGF-β1)及肝细胞生长因子(HGF)在肾间质的阳性染色,并进行半定量分析。结果与假手术组相比,模型组大鼠SCr、BUN、血浆AngⅡ,尿NAG、β2-MG水平以及α-SMA、FN、PAI-1、TGF-β1表达均显著升高(P<0.01)。与模型组相比,缬沙坦组大鼠SCr、BUN,尿NAG及β2-MG水平差异无统计学意义(P>0.05),但血浆AngⅡ及肾间质α-SMA、FN、PAI-1、TGF-β1表达均显著降低,HGF表达则显著增高(P<0.01)。结论缬沙坦虽然对UUO大鼠肾小球、肾小管功能改善不明显,但能抑制AngⅡ的生成,可能通过下调TGF-β1的过度表达,上调HGF的表达,抑制α-SMA、FN、PAI-1的表达,从而抑制肾小管上皮细胞间充质转分化(EMT),减少细胞外基质(ECM)沉积,达到改善RIF的作用。
关键词:  单侧输尿管梗阻  肾间质纤维化  血管紧张素Ⅱ  α-平滑肌肌动蛋白  转化生长因子β1  肝细胞生长因子
DOI:10.3724/SP.J.1008.2010.0278
投稿时间:2009-11-27修订日期:2010-02-09
基金项目:上海市重点学科建设项目(Y0302).
Effects of valsartan on renal interstitium fibrosis in rats after unilateral ureteral obstruction
ZHOU Jian-song1, CHEN Gang2, SHEN Ye-qu2, WU Mei2, HE Li-qun2*
(1. Department of Nephrology, the Third Affiliated Hospital of Nantong University, Wuxi 214041, Jiangsu, China;2. Department of Nephrology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China)
Abstract:
ObjectiveTo study the effect of valsartan, an angiotensinⅡtypeⅠreceptor antagonist(AT1RA), on renal interstitium fibrosis(RIF)in rats with unilateral ureteral obstruction (UUO), and to discuss the possible mechanisms. MethodsThirty-five Sprague-Dawley rats were randomly divided into sham-operation, model and valsartan groups.The rat UUO model was established. From the day after operation,the rats in sham-operation and model groups received intragastric valsartan and sodium chloride in tales doses. The serum creatinine(SCr), blood urea nitrogen(BUN), angiotensin-Ⅱ(AngⅡ) in blood plasma, N-acetyl-β-D-glucosaminidase(NAG)and 24 h urine β2-microglobulin(β2-MG)were examined 4 weeks after operation. The renal tissues of the obstructed sides were harvested; H-E staining and Masson staining were used to observe the tubulointerstitial lesions; and immunohistochemistry staining was used for semiquantitative analysis of alpha-smooth muscle actin(α-SMA), fibronectin(FN), plasminogen activator inhibitor-1(PAI-1), transforming growth factor-beta 1(TGF-β1), and hepatocyte growth factor(HGF).ResultsCompared with those in the sham-operation group, SCr, BUN, AngⅡ, NAG and β2-MG levels,and the expression of α-SMA,FN,PAI-1,and TGF-β1 in model group were significantly higher(P<0.01). The levels of SCr,BUN,NAG and β2-MG were comparable between valsartan group and the model group(P>0.05). The expression levels of α-SMA,FN,PAI-1,and TGF-β1 in valsartan group were significantly lower than and the expression of HGF was significantly higher than those in the model group(P<0.01). ConclusionValsartan does not improve the tubular and glomerular functions, but it can inhibit production of Ang-II. Valsartan may inhibit renal interstitial fibrosis by inhibiting renal tubule epithelial mesenchymal transdifferentiation and reducing extracellular matrix deposition through blocking up AngⅡ, inhibiting overexpression of α-SMA,FN,PAI-1, and TGF-β1, and inducing the HGF expression.
Key words:  unilateral ureteral obstruction  renal interstitium fibrosis  angiotensinⅡ  alpha-smooth muscle actin  transforming growth factor-beta 1  hepatocyte growth factor