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, Youhua Liu

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38 Scopus citations


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)-β1 using an in vitro cell culture system. In human mesangial cells 9-cis-RA suppressed TGF-β1-induced α-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 corepressor TGIF in mesangial cells. Overexpression of exogenous TGIF by transfection or 9-cis-RA treatment suppressed trans-activation of the TGF-β-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-β1 in mesangial cells and that 9-cis RA activity is likely mediated through a mechanism dependent on HGF/c-met receptor signaling.

Original languageEnglish (US)
Pages (from-to)947-957
Number of pages11
JournalAmerican Journal of Pathology
Issue number4
StatePublished - Oct 2005

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine


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