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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。
OBJECTIVE: Tubulointerstitial fibrosis (TIF) is an important common pathway for the progression of chronic kidney disease to end-stage renal disease (ESRD). Angiotensin Ⅱ AT1 receptor blocker losartan has a protective effect on chronic kidney disease, but whether it can inhibit tubulointerstitial fibrosis and its possible mechanism remains unclear. In this study, unilateral ureteral obstruction (UUO) rat model was established in vivo to observe the inhibitory effect of losartan on tubulointerstitial fibrosis and its possible mechanism. Methods: Fifty SD rats were divided into three groups: sham operation group (n = 10), UUO group (n = 20) and UUO losartan treatment group (n = 20). After losartan treatment group losartan intragastric administration, a dose of 20mg · kg-1 · d-1. Rats were sacrificed on the 7th day and the 14th day respectively. Immunofluorescence staining and Western blot analysis of E-cadherin, Vimentin, α-SMA, β-catenin and ZEB1 in frozen tissue were performed. Results: On the 7th day, the histopathological changes in the UUO group were enlargement of tubular lumen, atrophy of the tubule, widening of the interstitium and infiltration of inflammatory cells, some of tubulointerstitial fibrosis, and the more severe interstitial fibrosis on the 14th day . Compared with the control group, the expression of E-cadherin in the UUO model group was significantly decreased on the 7th day and the 14th day, while the expressions of Vimentin, α-SMA, β-catenin and ZEB1 were increased. Compared with UUO model group, the changes of tubulointerstitial fibrosis in UUO losartan treatment group were significantly reduced, the expression of E-cadherin in renal tissue increased, while the expressions of Vimentin, α-SMA, β-catenin and ZEB1 decreased. CONCLUSION: Losartan can inhibit tubulointerstitial fibrosis in rats, which may be related to the inhibition of the expression of β-catenin / ZEB1 by losartan.