Hepatocyte growth factor receptor signaling mediates the anti-fibrotic action of 9-cis-retinoic acid in glomerular mesangial cells.
Retinoic acid (RA), an active metabolite of vitamin A, plays a critical role in the regulation of cell proliferation, survival, and differentiation. RA action is primarily mediated through its receptors, ligand-dependent transcription factors of the steroid/thyroid/vitamin D nuclear receptor superfamily. Recent studies indicate that administration of RA mitigates progressive kidney disease, underscoring its renoprotective potential. In this study, we investigated the effects of 9-cis-RA on glomerular mesangial cell activation induced by transforming growth factor (TGF)-beta1 using an in vitro cell culture system. In human mesangial cells 9-cis-RA suppressed TGF-beta1-induced alpha-smooth muscle actin, fibronectin, and plasminogen activator inhibitor-1 expression, but it did not significantly affect cell proliferation and survival. Interestingly, 9-cis-RA induced hepatocyte growth factor (HGF) mRNA expression and protein secretion, stimulated HGF promoter activity, and activated c-met receptor phosphorylation. Similar to HGF, 9-cis-RA induced expression of the Smad transcriptional co-repressor TGIF in mesangial cells. Overexpression of exogenous TGIF by transfection or 9-cis-RA treatment suppressed trans-activation of the TGF-beta-responsive promoter. Moreover, conditional ablation of the c-met receptor completely abolished the anti-fibrotic effect of 9-cis-RA and abrogated TGIF induction. Collectively, these results indicate that 9-cis-RA possesses anti-fibrotic ability by antagonizing TGF-beta1 in mesangial cells and that 9-cis-RA activity is likely mediated through a mechanism dependent on HGF/c-met receptor signaling.
Wen
Xiaoyan
X
Department of Pathology, University of Pittsburgh School of Medicine, S-405 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, PA 15261, USA.
Li
Yingjian
Y
Hu
Kebin
K
Dai
Chunsun
C
Liu
Youhua
Y
D000199:Actins / Q000037:antagonists & inhibitors; D000256:Adenoviridae / Q000235:genetics; D000077556:Alitretinoin; D000818:Animals; D015153:Blotting, Western; D018929:Cell Culture Techniques; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D004305:Dose-Response Relationship, Drug; D005353:Fibronectins / Q000037:antagonists & inhibitors; D005355:Fibrosis / Q000188:drug therapy*; D019084:Fluorescent Antibody Technique, Indirect; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D012333:RNA, Messenger / Q000187:drug effects; D051381:Rats; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000494:pharmacology; D053773:Transforming Growth Factor beta1; D014212:Tretinoin / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
D000199:Actins; D000077556:Alitretinoin; D016895:Culture Media, Serum-Free; D005353:Fibronectins; D008156:Luciferases; D017395:Plasminogen Activator Inhibitor 1; D019859:Proto-Oncogene Proteins c-met; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014212:Tretinoin; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; C508962:Tgfb1 protein, rat; C498862:Acta2 protein, rat