Increased expression of p21WAF1/CIP1 in kidney proximal tubules mediates fibrosis.
Increased expression of p21WAF1/CIP1 in kidney proximal tubules mediates fibrosis.
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DOI：
10.1152/ajprenal.00489.2014
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发表时间：
2015-01
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影响因子：
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通讯作者：
J. Megyesi;A. Tarcsafalvi;Shenyang Li;Rawad Hodeify;N. S. H. L. Seng;D. Portilla;P. Price
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作者：
J. Megyesi;A. Tarcsafalvi;Shenyang Li;Rawad Hodeify;N. S. H. L. Seng;D. Portilla;P. Price
组织纤维化是发达国家死亡的主要原因。它通常发生在急性或慢性损伤后，影响多种器官，包括心脏、肝脏、肺和肾脏。利用慢性肾脏病的肾消融模型，我们之前发现进行性肾纤维化的发展依赖于p21（WAF1/Cip1）的表达； p21基因的基因敲除大大缓解了这种疾病。在本研究中，我们扩展了这一观察结果，并报告说，两种不同的急性肾脏损伤引起的纤维化也依赖于 p21。此外，当p21表达仅限于近端小管时，整个器官损伤后会诱导纤维化。我们描述的一种分子纤维化开关是转化生长因子-β 诱导，它发生在体内和暴露于表达 p21 的腺病毒的培养肾细胞中。我们的数据表明，纤维化是 p21 依赖性的，并且在应激后防止 p21 诱导可能是一个新的治疗靶点。
Tissue fibrosis is a major cause of death in developed countries. It commonly occurs after either acute or chronic injury and affects diverse organs, including the heart, liver, lung, and kidney. Using the renal ablation model of chronic kidney disease, we previously found that the development of progressive renal fibrosis was dependent on p21(WAF1/Cip1) expression; the genetic knockout of the p21 gene greatly alleviated this disease. In the present study, we expanded on this observation and report that fibrosis induced by two different acute injuries to the kidney is also dependent on p21. In addition, when p21 expression was restricted only to the proximal tubule, fibrosis after injury was induced in the whole organ. One molecular fibrogenic switch we describe is transforming growth factor-β induction, which occurred in vivo and in cultured kidney cells exposed to adenovirus expressing p21. Our data suggests that fibrosis is p21 dependent and that preventing p21 induction after stress could be a novel therapeutic target.