The microRNA miR-433 promotes renal fibrosis by amplifying the TGF-β/Smad3-Azin1 pathway
The microRNA miR-433 promotes renal fibrosis by amplifying the TGF-β/Smad3-Azin1 pathway
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DOI：
10.1038/ki.2013.272
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发表时间：
2013-12-01
影响因子：
19.6
通讯作者：
Lan, Hui Y.
中科院分区：
文献类型：
--
作者：
Li, Rong;Chung, Arthur C. K.;Lan, Hui Y.
TGF-β/Smad 3通路在组织纤维化中起主要作用，但确切机制尚未完全了解。在这里，我们确定microRNA miR-433是TGF-β/Smad 3驱动的肾纤维化的重要组成部分。miR-433在单侧输尿管梗阻（侵袭性肾纤维化模型）后上调。在体外，miR-433的过表达增强了TGF-β 1诱导的纤维化，而miR-433的敲低抑制了这种反应。此外，Smad 3，而不是Smad 2，结合到miR-433启动子，以诱导其表达。通过超声微泡介导的基因转移将miR-433敲低质粒递送至肾脏抑制了梗阻模型中纤维化的诱导和进展。抗酶抑制剂Azin 1是多胺合成的重要调节剂，被鉴定为miR-433的靶点。miR-433的过表达抑制了Azin 1的表达，而Azin 1的过表达反过来又抑制了TGF-β信号传导和纤维化反应。因此，miR-433是TGF-β/Smad 3诱导的肾纤维化的重要组成部分，通过诱导正反馈环放大TGF-β/Smad 3信号传导，并且可能是组织纤维化的潜在治疗靶点。
The TGF-beta/Smad3 pathway plays a major role in tissue fibrosis, but the precise mechanisms are not fully understood. Here we identified microRNA miR-433 as an important component of TGF-beta/Smad3-driven renal fibrosis. The miR-433 was upregulated following unilateral ureteral obstruction, a model of aggressive renal fibrosis. In vitro, overexpression of miR-433 enhanced TGF-beta 1-induced fibrosis, whereas knockdown of miR-433 suppressed this response. Furthermore, Smad3, but not Smad2, bound to the miR-433 promoter to induce its expression. Delivery of an miR-433 knockdown plasmid to the kidney by ultrasound microbubble-mediated gene transfer suppressed the induction and progression of fibrosis in the obstruction model. The antizyme inhibitor Azin1, an important regulator of polyamine synthesis, was identified as a target of miR-433. Overexpression of miR-433 suppressed Azin1 expression, while, in turn, Azin1 overexpression suppressed TGF-beta signaling and the fibrotic response. Thus, miR-433 is an important component of TGF-beta/Smad3-induced renal fibrosis through the induction of a positive feedback loop to amplify TGF-beta/Smad3 signaling, and may be a potential therapeutic target in tissue fibrosis.