title: Smad3-mediated upregulation of miR-21 promotes renal fibrosis.
abstract: TGF-β/Smad signaling plays a role in fibrogenesis, but therapies targeting TGF-β are ineffective in treating renal fibrosis. Here, we explored the therapeutic potential of targeting TGF-β-induced microRNA in the progression of renal fibrosis. Microarray analysis and real-time PCR revealed upregulation of miR-21 in tubular epithelial cells (TECs) in response to TGF-β. Lack of Smad3, but not lack of Smad2, prevented cells from upregulating miR-21 in response to TGF-β. In addition, Smad3-deficient mice were protected from upregulation of miR-21 and fibrosis in the unilateral ureteral obstruction model. In contrast, conditional knockout of Smad2 enhanced miR-21 expression and renal fibrosis. Furthermore, ultrasound-microbubble-mediated gene transfer of a miR-21-knockdown plasmid halted the progression of renal fibrosis in established obstructive nephropathy. In conclusion, these data demonstrate that Smad3, but not Smad2, signaling increases expression of miR-21, which promotes renal fibrosis. Inhibition of miR-21 may be a therapeutic approach to suppress renal fibrosis.
authors.affiliation: Li Ka Shing Institute of Health Sciences, Department of Chemical Pathology, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhong
authors.forename: Arthur C K
authors.initials: AC
authors.lastname: Chung
authors.forename: Hai-Yong
authors.initials: HY
authors.lastname: Chen
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Meng
authors.forename: Hui Y
authors.initials: HY
authors.lastname: Lan
mesh_terms: D000818:Animals; D002460:Cell Line; D018450:Disease Progression; D055785:Gene Knockdown Techniques; D018014:Gene Transfer Techniques; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009400:Nephrosclerosis / Q000378:metabolism*; D051381:Rats; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; D051899:Smad2 Protein; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C497787:Smad3 protein, rat; D016212:Transforming Growth Factor beta; C546082:mirn21 microRNA, rat