title: miR-192 mediates TGF-beta/Smad3-driven renal fibrosis.
abstract: 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-beta1-induced miR-192 expression. Furthermore, Smad3 but not Smad2 mediated TGF-beta1-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-beta1-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.
authors.affiliation: Department of Medicine and Therapeutics and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Arthur C K
authors.initials: AC
authors.lastname: Chung
authors.forename: Xiao R
authors.initials: XR
authors.lastname: Huang
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Meng
authors.forename: Hui Y
authors.initials: HY
authors.lastname: Lan
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005355:Fibrosis / Q000209:etiology; D007668:Kidney / Q000473:pathology*; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D051381:Rats; D051900:Smad3 Protein / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: D035683:MicroRNAs; C539618:Mirn192 microRNA, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta