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(American Journal of Pathology. 2005;167:947-957.)
© 2005 American Society for Investigative Pathology

Hepatocyte Growth Factor Receptor Signaling Mediates the Anti-Fibrotic Action of 9-cis-Retinoic Acid in Glomerular Mesangial Cells

Xiaoyan Wen, Yingjian Li, Kebin Hu, Chunsun Dai and Youhua Liu

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

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)-ß1 using an in vitro cell culture system. In human mesangial cells 9-cis-RA suppressed TGF-ß1-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-ß-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-ß1 in mesangial cells and that 9-cis-RA activity is likely mediated through a mechanism dependent on HGF/c-met receptor signaling.




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