Hepatocyte growth factor receptor signaling mediates the anti-fibrotic action of 9-cis-retinoic acid in glomerular mesangial cells
Hepatocyte growth factor receptor signaling mediates the anti-fibrotic action of 9-cis-retinoic acid in glomerular mesangial cells
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DOI：
10.1016/s0002-9440(10)61185-6
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发表时间：
2005-10-01
影响因子：
6
通讯作者：
Liu, YH
中科院分区：
文献类型：
--
作者：
Wen, XY;Li, YJ;Liu, YH
维甲酸（RA）是维生素A的活性代谢产物，在调节细胞增殖、存活和分化中起着关键作用。RA的作用主要是通过其受体介导的，这些受体是类固醇/甲状腺/维生素D核受体超家族的配体依赖性转录因子。最近的研究表明，RA的管理减轻进行性肾脏疾病，强调其肾脏保护潜力。在这项研究中，我们研究了9-顺式RA对转化生长因子（TGF）-β 1诱导的肾小球系膜细胞活化的影响，使用体外细胞培养系统。在人肾小球系膜细胞中，9-cis-RA抑制TGF-β 1诱导的α-平滑肌肌动蛋白、纤连蛋白和纤溶酶原激活物抑制剂-1的表达，但对细胞增殖和存活没有显著影响。有趣的是，9-cis-RA诱导肝细胞生长因子（HGF）的mRNA表达和蛋白分泌，刺激HGF启动子活性，并激活c-met受体磷酸化。与HGF类似，9-cis-RA诱导系膜细胞表达Smad转录辅抑制因子TGIF。通过转染或9-cis-RA处理过表达外源性TGIF抑制了TGF-β应答启动子的反式激活。此外，cmet受体的条件性消融完全消除了9-cis-RA的抗纤维化作用，并消除了TGIF诱导。总的来说，这些结果表明，9-顺式-RA具有抗纤维化的能力，通过拮抗TGF-β 1在肾小球系膜细胞和9-顺式-RA活性可能是通过一种机制介导的依赖于HGF/c-met受体信号转导。
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 reno-protective potential. In this study, we investigated the effects of 9-cis-RA on glomerular mesangial cell activation induced by transforming growth factor (TGF)-beta 1 using an in vitro cell culture system. In human mesangial cells 9-cis-RA suppressed TGF-beta 1-induced a-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-beta-responsive promoter. Moreover, conditional ablation of the cmet 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-beta 1 in mesangial cells and that 9-cis-RA activity is likely mediated through a mechanism dependent on HGF/c-met receptor signaling.