Hepatocyte growth factor suppresses renal interstitial myofibroblast activation and intercepts Smad signal transduction.
Interstitial myofibroblasts are alpha-smooth muscle actin-positive cells that play a crucial role in the accumulation of excess extracellular matrix during renal interstitial fibrogenesis. Despite their importance in the pathogenesis of renal fibrosis, relatively little is known about the regulators and the mechanism controlling the activation of renal interstitial myofibroblasts in disease conditions. Here, we show that hepatocyte growth factor (HGF) acts as a potent inhibitor of the transforming growth factor (TGF)-beta1-mediated myofibroblastic activation from normal rat renal interstitial fibroblasts (NRK-49F). Simultaneous incubation of HGF abolished TGF-beta1-induced de novo alpha-smooth muscle actin expression, F-actin reorganization, and interstitial collagen I overproduction in a dose-dependent manner. To decipher the mechanism underlying HGF antagonizing TGF-beta1's action, we examined the effects of HGF on TGF-beta1-mediated Smad signaling. HGF neither inhibited Smad-2/3 phosphorylation and their association with Smad-4 induced by TGF-beta1, nor significantly affected inhibitory Smad-6 and -7 expression and cellular abundance of Smad transcriptional co-repressors in NRK-49F cells. However, pretreatment with HGF markedly attenuated activated Smad-2/3 nuclear translocation and accumulation. This action of HGF was apparently dependent on HGF-mediated extracellular signal-regulated kinase-1 and -2 (Erk-1/2) phosphorylation and activation. Inhibition of Erk-1/2 activation by Mek kinase inhibitor PD98059 restored TGF-beta1-mediated Smad-2/3 nuclear accumulation and myofibroblast activation. In vivo, HGF selectively blocked Smad-2/3 nuclear accumulation in renal interstitial cells in the fibrotic kidneys induced by unilateral ureteral obstruction. Therefore, HGF suppresses TGF-beta1-mediated renal interstitial myofibroblastic activation; and this action of HGF is likely related to a mitogen-activated protein kinase-dependent blockade of Smad nuclear translocation.
Yang
Junwei
J
Department of Pathology, Division of Cellular and Molecular Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Dai
Chunsun
C
Liu
Youhua
Y
D000199:Actins / Q000378:metabolism; D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D002460:Cell Line; D024042:Collagen Type I / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D005355:Fibrosis / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*; D051785:Smad Proteins; D015534:Trans-Activators / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D014746:Vimentin / Q000378:metabolism
D000199:Actins; D024042:Collagen Type I; D004268:DNA-Binding Proteins; D051785:Smad Proteins; C508960:TGFB1 protein, human; C508962:Tgfb1 protein, rat; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014746:Vimentin; D017228:Hepatocyte Growth Factor; D020928:Mitogen-Activated Protein Kinases