title: MicroRNA-196a/b Mitigate Renal Fibrosis by Targeting TGF-β Receptor 2.
abstract: Organ-specific microRNAs have essential roles in maintaining normal organ function. However, the microRNA profile of the kidney and the role of microRNAs in modulating renal function remain undefined. We performed an unbiased assessment of the genome-wide microRNA expression profile in 14 mouse organs using Solexa deep sequencing and found that microRNA-196a (miR-196a) and miR-196b are selectively expressed in kidney, with 74.37% of mouse total miR-196a and 73.19% of mouse total miR-196b distributed in the kidneys. We confirmed the predominant expression of miR-196a/b in mouse and human kidney, particularly in the glomeruli and tubular epithelium, by quantitative RT-PCR and in situ hybridization assays. During unilateral ureteral obstruction (UUO)-induced mouse renal fibrosis, renal miR-196a/b levels rapidly decreased. Elevation of renal miR-196a/b expression by hydrodynamic-based delivery of a miR-196a/b-expressing plasmid before or shortly after UUO significantly downregulated profibrotic proteins, including collagen 1 and α-smooth muscle actin, and mitigated UUO-induced renal fibrosis. In contrast, depletion of renal miR-196a/b by miR-196a/b antagomirs substantially aggravated UUO-induced renal fibrosis. Mechanistic studies further identified transforming growth factor beta receptor II (TGFβR2) as a common target of miR-196a and miR-196b. Decreasing miR-196a/b expression in human HK2 cells strongly activated TGF-β-Smad signaling and cell fibrosis; whereas increasing miR-196a/b levels in mouse primary cultured tubular epithelial cells inhibited TGF-β-Smad signaling. In the UUO model, miR-196a/b silenced TGF-β-Smad signaling, decreased the expression of collagen 1 and α-smooth muscle actin, and attenuated renal fibrosis. Our findings suggest that elevating renal miR-196a/b levels may be a novel therapeutic strategy for treating renal fibrosis.
authors.affiliation: National Clinical Research Center of Kidney Diseases, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China; and.
authors.forename: Jiao
authors.initials: J
authors.lastname: Meng
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, School of Life Science, Nanjing University, Nanjing, China.
authors.forename: Limin
authors.initials: L
authors.lastname: Li
authors.affiliation: National Clinical Research Center of Kidney Diseases, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China; and.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, School of Life Science, Nanjing University, Nanjing, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: National Clinical Research Center of Kidney Diseases, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China; and.
authors.forename: Mingchao
authors.initials: M
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, School of Life Science, Nanjing University, Nanjing, China.
authors.forename: Donghai
authors.initials: D
authors.lastname: Li
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, School of Life Science, Nanjing University, Nanjing, China.
authors.forename: Chen-Yu
authors.initials: CY
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, School of Life Science, Nanjing University, Nanjing, China liuzhihong@nju.edu.cn kzen@nju.edu.cn.
authors.forename: Ke
authors.initials: K
authors.lastname: Zen
authors.affiliation: National Clinical Research Center of Kidney Diseases, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China; and liuzhihong@nju.edu.cn kzen@nju.edu.cn.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Liu
mesh_terms: D000818:Animals; D005260:Female; D005355:Fibrosis / Q000235:genetics; D006801:Humans; D007668:Kidney / Q000473:pathology*; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D008875:Middle Aged; D018125:Receptors, Transforming Growth Factor beta / Q000502:physiology*; D014517:Ureteral Obstruction / Q000235:genetics
chemical_list: C542543:MIRN196 microRNA, human; C000602251:MIRN196 microRNA, mouse; D035683:MicroRNAs; D018125:Receptors, Transforming Growth Factor beta
keywords: TGFβR2; microRNA; renal fibrosis