期刊
KIDNEY INTERNATIONAL
卷 84, 期 6, 页码 1129-1144出版社
ELSEVIER SCIENCE INC
DOI: 10.1038/ki.2013.272
关键词
microRNA therapy; miR-433; renal fibrosis; TGF-beta signaling
资金
- Research Grant Council of Hong Kong [RGC GRF 468711, 469110, 768409, CUHK5/CRF/09, CUHK3/CRF/12R, GRF 463612, 464010, 763908, 764109]
- Chinese University of Hong Kong [2010.2.025, 2011.1.076, 2012.1.021]
- Hong Kong Society of Nephrology [6903213]
- National Natural Science Foundation of China [81170681]
- Municipal Science and Technology R&D funding of basic research, Shenzhen [JC201104220290A]
- Major State Basic Research Development Program of China (973 program) [2012CB517700]
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.
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