miR-192 Mediates TGF-β/Smad3-Driven Renal Fibrosis : Journal of the American Society of Nephrology (original) (raw)
Basic Research
Department of Medicine and Therapeutics and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China
Correspondence: Dr. Hui Y. Lan, Department of Medicine and Therapeutics and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong, China. Phone: 852-3763-6077; Fax: 852-2145-7190; E-mail: [email protected]
Received February 2, 2010
Accepted March 24, 2010
Abstract
TGF-β/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-β/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-β/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-β1–induced miR-192 expression. Furthermore, Smad3 but not Smad2 mediated TGF-β1–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-β1–induced collagen matrix expression. Taken together, miR-192 may be a critical downstream mediator of TGF-β/Smad3 signaling in the development of renal fibrosis.
Copyright © 2010 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
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