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

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

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
Volume167
Issue number4
DOIs
StatePublished - Jan 1 2005

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Proto-Oncogene Proteins c-met
Mesangial Cells
Hepatocyte Growth Factor
Transforming Growth Factors
Tretinoin
Cell Survival
Cell Proliferation
Co-Repressor Proteins
Calcitriol Receptors
alitretinoin
Plasminogen Activator Inhibitor 1
Kidney Diseases
Cytoplasmic and Nuclear Receptors
Vitamin A
Fibronectins
Transfection
Smooth Muscle
Actins
Cell Differentiation
Thyroid Gland

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

Cite this

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title = "Hepatocyte growth factor receptor signaling mediates the anti-fibrotic action of 9-cis-retinoic acid in glomerular mesangial cells",
abstract = "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.",
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Hepatocyte growth factor receptor signaling mediates the anti-fibrotic action of 9-cis-retinoic acid in glomerular mesangial cells. / Wen, Xiaoyan; Li, Yingjian; Hu, Kebin; Dai, Chunsun; Liu, Youhua.

In: American Journal of Pathology, Vol. 167, No. 4, 01.01.2005, p. 947-957.

Research output: Contribution to journalArticle

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AU - Wen, Xiaoyan

AU - Li, Yingjian

AU - Hu, Kebin

AU - Dai, Chunsun

AU - Liu, Youhua

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