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。
Objective To 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.Methods Thirty-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）.Results Compared 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（P0.01）.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（P0.01）.Conclusion Valsartan 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.
出处
《第二军医大学学报》
CAS
CSCD
北大核心
2010年第3期278-282,共5页
Academic Journal of Second Military Medical University
基金
上海市重点学科建设项目(Y0302)~~
