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Hepatocyte Growth Factor Antagonizes the Profibrotic Action of TGF-1 in Mesangial Cells by Stabilizing Smad Transcriptional Corepressor TGIF

Division of Cellular and Molecular Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Correspondence to Dr. Youhua Liu, Department of Pathology, University of Pittsburgh School of Medicine, S-405 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15261. Phone: 412-648-8253; Fax: 412-648-1916; E-mail: liuy{at}upmc.edu

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-1 were investigated. Western blot analysis and immunostaining revealed that HGF suppressed -smooth muscle actin expression induced by TGF-1 in cultured rat and human mesangial cells. HGF also inhibited TGF-1–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-1–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-1–responsive promoter activity and completely blocked TGF-1–induced -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-1 in mesangial cells by stabilizing Smad transcriptional corepressor TGIF.

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