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目的:探讨Smad泛素化调节因子2(Smurf2)在小鼠单侧输尿管梗阻所致肾间质纤维化进展中的作用机制。方法:采用结扎雄性CD-1小鼠单侧输尿管(UUO)的方法建立肾间质纤维化动物模型,设假手术为对照组(Sham组)。术后3、7、14 d处死小鼠。用常规病理染色法观察两组小鼠肾组织形态和肾间质纤维化程度;以免疫蛋白印迹及免疫组织化学染色法检测两组小鼠肾组织中Smurf2、E-钙黏蛋白(E-cadherin)、α-平滑肌肌动蛋白(α-SMA)和纤维连接素(FN)的表达和分布。结果:与Sham组相比,UUO术后7 d小鼠出现部分肾小管扩张、萎缩和肾间质纤维化。同时,UUO术后肾组织中Smurf2、α-SMA和FN表达呈时间依赖性升高,E-cadherin表达则明显下降。并且,Smurf2蛋白主要分布于肾小管上皮细胞核内;α-SMA分布于肾小管上皮细胞和肾间质中;FN则分布于肾间质中。相关回归分析表明:UUO术后小鼠肾组织内Smurf2表达与α-SMA(r=0.765,P<0.001)和FN蛋白水平呈正相关(r=0.773,P<0.001);与E-cadherin表达呈负相关(r=-0.656,P<0.001)。结论:梗阻性肾病小鼠肾组织中Smurf2可能通过诱导肾小管EMT形成促进肾间质纤维化的进展。
Objective: To investigate the mechanism of Smad2 in the development of renal interstitial fibrosis induced by unilateral ureteral obstruction in mice. Methods: Animal models of renal interstitial fibrosis were established by ligation of unilateral ureteral catheter (UUO) in male CD-1 mice. Sham-operated rats were used as control group (sham group). Mice were sacrificed 3, 7 and 14 days after operation. The morphological changes of renal tissue and the degree of renal interstitial fibrosis were observed by routine pathological staining method. The expressions of Smurf2, E-cadherin (E-cadherin) in renal tissue of the two groups were detected by Western blotting and immunohistochemical staining ), Α-smooth muscle actin (α-SMA) and fibronectin (FN). Results: Compared with Sham group, some tubules were dilated, atrophied and interstitial fibrosis in UUO 7 days after operation. At the same time, the expression of Smurf2, α-SMA and FN in renal tissue of UUO increased in a time-dependent manner, while the expression of E-cadherin decreased significantly. Smurf2 protein is mainly distributed in the nucleus of renal tubular epithelial cells; α-SMA is distributed in renal tubular epithelial cells and renal interstitium; FN is distributed in renal interstitium. Correlation analysis showed that there was a positive correlation between the expression of Smurf2 and the expression of α-SMA (r = 0.765, P <0.001) and FN protein in UUO postoperative rats (r = 0.773, P <0.001) Negative correlation (r = -0.656, P <0.001). Conclusion: Smurf2 in renal tissue of obstructive nephropathy mice may promote the progress of renal interstitial fibrosis by inducing the formation of renal tubular EMT.