Blockage of tubular epithelial to myofibroblast transition by hepatocyte growth factor prevents renal interstitial fibrosis.
Activation of alpha-smooth muscle actin-positive myofibroblast cells is a key event in the progression of chronic renal diseases that leads to end-stage renal failure. Although the origin of these myofibroblasts in the kidney remains uncertain, emerging evidence suggests that renal myofibroblasts may derive from tubular epithelial cells by a process of epithelial to mesenchymal transition. It was demonstrated that hepatocyte growth factor (HGF) exhibited a remarkable ability to block this phenotypic transition both in vitro and in vivo. HGF abrogated the alpha-smooth muscle actin expression and E-cadherin depression triggered by transforming growth factor-beta1 in tubular epithelial cells in a dose-dependent manner. HGF also blocked morphologic transformation of tubular epithelial cells and inhibited the expression and extracellular deposition of fibronectin. In a mouse model of renal fibrosis disease induced by unilateral ureteral obstruction, transforming growth factor-beta type I receptor expression was specifically increased in renal tubules, and myofibroblastically phenotypic transition of the tubules was evident in vivo. Remarkably, injections of exogenous HGF blocked myofibroblast activation and drastically prevented renal interstitial fibrosis in the obstructed kidneys. These results suggest that tubular epithelial to myofibroblast conversion may play an important role in the pathogenesis of renal fibrosis and that blocking this phenotypic transition could provide a novel therapeutic strategy for the treatment of fibrotic diseases.
Yang
Junwei
J
Division of Cellular and Molecular Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Liu
Youhua
Y
Division of Cellular and Molecular Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
D000199:Actins / Q000037:antagonists & inhibitors; D000818:Animals; D015820:Cadherins / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology*; D005355:Fibrosis / Q000517:prevention & control; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D007674:Kidney Diseases / Q000473:pathology / Q000517:prevention & control*; D007684:Kidney Tubules / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D009132:Muscles / Q000166:cytology*; D010641:Phenotype; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053773:Transforming Growth Factor beta1
D000199:Actins; D015820:Cadherins; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D017228:Hepatocyte Growth Factor