1] Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China [2] Department of Chemical Pathology, The Chinese University of Hong Kong, Hong Kong, China [3] Department of Nephrology, First People's Hospital of Yunnan Province, Yunnan, China.
Kidney Int. 2013 Dec;84(6):1129-44. doi: 10.1038/ki.2013.272. Epub 2013 Jul 17.
The TGF-β/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-β/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-β1-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-β signaling and the fibrotic response. Thus, miR-433 is an important component of TGF-β/Smad3-induced renal fibrosis through the induction of a positive feedback loop to amplify TGF-β/Smad3 signaling, and may be a potential therapeutic target in tissue fibrosis.
TGF-β/Smad3 通路在组织纤维化中起着重要作用，但确切的机制尚不完全清楚。在这里，我们将 microRNA miR-433 鉴定为 TGF-β/Smad3 驱动的肾脏纤维化的重要组成部分。miR-433 在单侧输尿管梗阻（一种侵袭性肾脏纤维化模型）后上调。在体外，miR-433 的过表达增强了 TGF-β1 诱导的纤维化，而 miR-433 的敲低则抑制了这种反应。此外，Smad3 而不是 Smad2 与 miR-433 启动子结合以诱导其表达。通过超声微泡介导的基因转移将 miR-433 敲低质粒递送到肾脏中，抑制了梗阻模型中纤维化的诱导和进展。抗酶抑制剂 Azin1 是多胺合成的重要调节剂，被鉴定为 miR-433 的靶标。miR-433 的过表达抑制了 Azin1 的表达，而 Azin1 的过表达反过来又抑制了 TGF-β 信号和纤维化反应。因此，miR-433 通过诱导正反馈环来放大 TGF-β/Smad3 信号，是 TGF-β/Smad3 诱导的肾脏纤维化的重要组成部分，可能是组织纤维化的潜在治疗靶点。
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