氯沙坦对肾间质纤维化的抑制作用

目的:肾小管间质纤维化(tubulointerstitial fibrosis,TIF)是慢性肾脏病进展为终末期肾病(end-stage renaldisease,ESRD)的重要共同通路。血管紧张素ⅡAT1受体阻断剂--氯沙坦对慢性肾脏病具有保护作用,但其能否抑制肾小管间质纤维化及其可能的机制尚不清楚。本实验通过在体内构建单侧输尿管梗阻(unilateral ureteral obstruction,UUO)大鼠模型,观察氯沙坦对肾小管间质纤维化的抑制作用及其可能机制。方法:50只SD大鼠分为3组:假手术组(n=10),UUO组(n=20),UUO氯沙坦治疗组(n=20)。术后氯沙坦治疗组予以氯沙坦灌胃,剂量20mg·kg-1·d-1。分别在术后第7天、第14天处死大鼠。冰冻组织行E-cadherin,Vimentin,α-SMA,β-catenin和ZEB1免疫荧光染色及Western blot分析。结果:UUO组大鼠第7天组织病理学改变为肾小管管腔扩大,小管萎缩,间质增宽及炎细胞浸润,部分小管间质纤维化;第14天间质纤维化表现更为严重。与对照组相比,UUO模型组大鼠第7天、第14天肾间质上皮标志物E-cadherin表达显著下降,而Vimentin,α-SMA,β-catenin和ZEB1表达增加。与UUO模型组比较,UUO氯沙坦治疗组大鼠肾小管间质纤维化改变明显减轻,肾组织E-cadherin表达增加,Vimentin,α-SMA,β-catenin和ZEB1的表达减少。结论:氯沙坦可抑制大鼠体内的肾小管间质纤维化,其机制可能与氯沙坦抑制小管上皮间充质转化相关因子β-catenin/ZEB1的表达有关。

Inhibitory Effect of Losartan on Renal Tubulointerstitial Fibrosis in Vivo

Objective:Tubulointerstitial fibrosis(TIF) has evolved as the important common process underlying the progression of chronic kidney disease(CKD) to end-stage renal disease(ESRD).Losartan has been demonstrated to be protective in chronic kidney disease,but whether it can inhibit TIF and its possible mechanism remain uncertain.Here,we investigated the effects of losartan on TIF in a unilateral ureteral obstruction(UUO) rat model in vivo.Methods:Fifty Sprague-Dawley rats were randomly divided into three groups:sham operation(n=10),UUO model(n=20),and UUO with losartan treatment(n=20).Rats were sacrificed seven and 14 days after surgery.Expression of E-cadherin,vimentin,α-smooth muscle actin(SMA),β-catenin,and ZEB1 in rat kidney tissue was detected by immunofluorescence staining and Western blot.Results:Renal pathological changes and TIF were lighter in losartan-treated UUO rats compared with that in the UUO models,and losartan partly maintained E-cadherin expression and suppressed expression of vimentin,α-SMA,β-catenin,and ZEB1 at different times.Conclusion:These results suggest that losartan inhibits TIF in vivo,possibly by inhibiting the β-catenin/ZEB1 pathway