title: Transforming growth factor β1 (TGF-β1) enhances expression of profibrotic genes through a novel signaling cascade and microRNAs in renal mesangial cells.
abstract: Increased expression of transforming growth factor-β1 (TGF-β1) in glomerular mesangial cells (MC) augments extracellular matrix accumulation and hypertrophy during the progression of diabetic nephropathy (DN), a debilitating renal complication of diabetes. MicroRNAs (miRNAs) play key roles in the pathogenesis of DN by modulating the actions of TGF-β1 to enhance the expression of profibrotic genes like collagen. In this study, we found a significant decrease in the expression of miR-130b in mouse MC treated with TGF-β1. In parallel, there was a down-regulation in miR-130b host gene 2610318N02RIK (RIK), suggesting host gene-dependent expression of this miRNA. TGF-β receptor 1 (TGF-βR1) was identified as a target of miR-130b. Interestingly, the RIK promoter contains three NF-Y binding sites and was regulated by NF-YC. Furthermore, NF-YC expression was inhibited by TGF-β1, suggesting that a signaling cascade, involving TGF-β1-induced decreases in NF-YC, RIK, and miR-130b, may up-regulate TGF-βR1 to augment expression of TGF-β1 target fibrotic genes. miR-130b was down-regulated, whereas TGF-βR1, as well as the profibrotic genes collagen type IV α 1 (Col4a1), Col12a1, CTGF, and PAI-1 were up-regulated not only in mouse MC treated with TGF-β1 but also in the glomeruli of streptozotocin-injected diabetic mice, supporting in vivo relevance. Together, these results demonstrate a novel miRNA- and host gene-mediated amplifying cascade initiated by TGF-β1 that results in the up-regulation of profibrotic factors, such as TGF-βR1 and collagens associated with the progression of DN.
authors.affiliation: From the Department of Diabetes and Division of Molecular Diabetes Research and.
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Castro
authors.affiliation: From the Department of Diabetes and Division of Molecular Diabetes Research and.
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Kato
authors.affiliation: From the Department of Diabetes and Division of Molecular Diabetes Research and the Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of the City of Hope, Duarte, California 91010 and.
authors.forename: Jung Tak
authors.initials: JT
authors.lastname: Park
authors.affiliation: From the Department of Diabetes and Division of Molecular Diabetes Research and the Department of Internal Medicine, College of Medicine, Yonsei University, 120-752 Seoul, Korea RNatarajan@coh.org.
authors.forename: Rama
authors.initials: R
authors.lastname: Natarajan
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D023081:CCAAT-Binding Factor / Q000378:metabolism; D002478:Cells, Cultured; D024141:Collagen Type IV / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000378:metabolism*; D018450:Disease Progression; D005355:Fibrosis; D005786:Gene Expression Regulation; D007668:Kidney / Q000378:metabolism; D050527:Mesangial Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*
chemical_list: D020413:3' Untranslated Regions; D023081:CCAAT-Binding Factor; D024141:Collagen Type IV; C582652:MIRN130 microRNA, mouse; D035683:MicroRNAs; D018125:Receptors, Transforming Growth Factor beta; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; C542687:mirnlet7 microRNA, mouse; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I
keywords: Collagen; Diabetes; Kidney; MicroRNA (miRNA); Signaling