title: Hepatocyte growth factor antagonizes the profibrotic action of TGF-beta1 in mesangial cells by stabilizing Smad transcriptional corepressor TGIF.
abstract: Mesangial cell activation is a predominant pathologic feature of diabetic nephropathy that precedes the accumulation of extracellular matrix leading to glomerulosclerosis. For understanding the potential mechanism by which hepatocyte growth factor (HGF) ameliorates diabetic nephropathy, the effects of HGF on mesangial cell activation induced by TGF-beta1 were investigated. Western blot analysis and immunostaining revealed that HGF suppressed alpha-smooth muscle actin expression induced by TGF-beta1 in cultured rat and human mesangial cells. HGF also inhibited TGF-beta1-mediated fibronectin and type I collagen expression. Such action of HGF was dependent on the activation of extracellular signal-regulated kinase-1 and -2 but not on Akt and p38 mitogen-activated protein kinase. HGF did not affect TGF-beta1-mediated Smad2 phosphorylation and its nuclear translocation. However, it rapidly upregulated Smad transcriptional corepressor TG-interacting factor (TGIF) abundance in mesangial cells, which was primarily mediated by stabilizing its protein from degradation. Ectopic expression of TGIF markedly suppressed Smad-mediated activation of TGF-beta1-responsive promoter activity and completely blocked TGF-beta1-induced alpha-smooth muscle actin expression. In vivo, TGIF expression was dramatically downregulated in the glomeruli of diabetic kidneys, and delivery of exogenous HGF induced TGIF expression. These results suggest that HGF specifically antagonizes the profibrotic action of TGF-beta1 in mesangial cells by stabilizing Smad transcriptional corepressor TGIF.
authors.affiliation: Division of Cellular and Molecular Pathology, Department of Pathology, University of Pittsburgh School of Medicine, 200 Lothrop Sttreet, Pittsburgh, PA 15261, USA.
authors.forename: Chunsun
authors.initials: C
authors.lastname: Dai
authors.forename: Youhua
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000199:Actins / Q000378:metabolism; D021581:Active Transport, Cell Nucleus; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005353:Fibronectins / Q000378:metabolism; D019084:Fluorescent Antibody Technique, Indirect; D005920:Glomerular Mesangium / Q000166:cytology* / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009130:Muscle, Smooth / Q000378:metabolism; D010766:Phosphorylation; D011233:Precipitin Tests; D021381:Protein Transport; D051381:Rats; D012097:Repressor Proteins / Q000378:metabolism*; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D000199:Actins; D004791:Enzyme Inhibitors; D005353:Fibronectins; D018398:Homeodomain Proteins; D012097:Repressor Proteins; C508960:TGFB1 protein, human; C097504:TGIF1 protein, human; C508961:Tgfb1 protein, mouse; C508962:Tgfb1 protein, rat; C490797:Tgif1 protein, mouse; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D017228:Hepatocyte Growth Factor; D004247:DNA; D008156:Luciferases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases