miR-192 Mediates TGF-β/Smad3-Driven Renal Fibrosis
miR-192 Mediates TGF-β/Smad3-Driven Renal Fibrosis
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DOI：
10.1681/asn.2010020134
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发表时间：
2010-08-01
影响因子：
13.6
通讯作者：
Lan, Hui Y.
中科院分区：
文献类型：
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作者：
Chung, Arthur C. K.;Huang, Xiao R.;Lan, Hui Y.
TGF-β/Smad 3促进肾纤维化，但调节促纤维化基因的机制仍不清楚。我们推测，miR-192，一种在肾脏中表达的microRNA，可能以Smad 3依赖的方式介导肾纤维化。微阵列和实时PCR证实了纤维化肾脏中miR-192的上调与TGF-β/Smad信号传导的激活之间的紧密关联。Smad 7的缺失促进了miR-192的表达，并增强了阻塞性肾病中的Smad信号传导和纤维化。相反，在大鼠5/6肾切除模型中，过表达Smad 7以阻断TGF-β/Smad信号传导抑制miR-192表达和肾纤维化;在体外，在肾小管上皮细胞中过表达Smad 7消除TGF-β 1诱导的miR-192表达。此外，Smad 3而不是Smad 2通过与miR-192启动子结合介导TGF-β 1诱导的miR-192表达。最后，miR-192模拟物的过表达促进了TGF-β 1诱导的胶原基质表达，而miR-192抑制剂的加入阻断了TGF-β 1诱导的胶原基质表达。总之，miR-192可能是肾纤维化发展中TGF-β/Smad 3信号传导的关键下游介质。
TGF-beta/Smad3 promotes renal fibrosis, but the mechanisms that regulate profibrotic genes remain unclear. We hypothesized that miR-192, a microRNA expressed in the kidney may mediate renal fibrosis in a Smad3-dependent manner. Microarray and real-time PCR demonstrated a tight association between upregulation of miR-192 in the fibrotic kidney and activation of TGF-beta/Smad signaling. Deletion of Smad7 promoted miR-192 expression and enhanced Smad signaling and fibrosis in obstructive kidney disease. In contrast, overexpression of Smad7 to block TGF-beta/Smad signaling inhibited miR-192 expression and renal fibrosis in the rat 5/6 nephrectomy model; in vitro, overexpression of Smad7 in tubular epithelial cells abolished TGF-beta 1-induced miR-192 expression. Furthermore, Smad3 but not Smad2 mediated TGF-beta 1-induced miR-192 expression by binding to the miR-192 promoter Last, overexpression of a miR-192 mimic promoted and addition of a miR-192 inhibitor blocked TGF-beta 1-induced collagen matrix expression. Taken together, miR-192 may be a critical downstream mediator of TGF-beta/Smad3 signaling in the development of renal fibrosis.