Hepatocyte growth factor antagonizes the profibrotic action of TGF-β1 in mesangial cells by stabilizing smad transcriptional corepressor TGIF
Hepatocyte growth factor antagonizes the profibrotic action of TGF-β1 in mesangial cells by stabilizing smad transcriptional corepressor TGIF
复制标题
DOI：
10.1097/01.asn.0000130568.53923.fd
复制
发表时间：
2004-06-01
影响因子：
13.6
通讯作者：
Liu, YH
中科院分区：
文献类型：
--
作者：
Dai, CS;Liu, YH
系膜细胞激活是糖尿病肾病的主要病理特征，它先于细胞外基质的积聚而导致肾小球硬化。为了解肝细胞生长因子(HGF)改善糖尿病肾病的可能机制，观察了HGF对转化生长因子-β1诱导的系膜细胞活化的影响。免疫印迹和免疫染色结果显示，HGF可抑制转化生长因子-β1诱导的大鼠和人肾小球系膜细胞α-平滑肌肌动蛋白的表达。HGF还可抑制转化生长因子-β1介导的纤维连接蛋白和I型胶原的表达。HGF的这种作用依赖于细胞外信号调节激酶-1和-2的激活，而不依赖于Akt和p38丝裂原激活的蛋白激酶。HGF不影响转化生长因子-β1介导的Smad2的磷酸化及其核转位。然而，它迅速上调了系膜细胞中Smad转录辅阻遏子TG相互作用因子(TGIF)的丰度，这主要是通过稳定其蛋白质的降解来实现的。TGIF的异位表达显著抑制Smad介导的转化生长因子-β1反应性启动子活性的激活，并完全阻断转化生长因子-β1诱导的α-平滑肌肌动蛋白表达。在体内，TGIF在糖尿病肾小球中的表达显著下调，外源性HGF可诱导TGIF的表达。这些结果提示，HGF通过稳定Smad转录辅阻遏子TGIF，特异性拮抗转化生长因子-β1对系膜细胞的促纤维化作用。
Mesangial cell activation is a predominant pathologic feature of diabetic nephropathy that precedes the accumulation of extracellular matrix leading to glomerulosclerosis. For understanding the potential mechanism by which hepatocyte growth factor (HGF) ameliorates diabetic nephropathy, the effects of HGF on mesangial cell activation induced by TGF-beta1 were investigated. Western blot analysis and immunostaining revealed that HGF suppressed a-smooth muscle actin expression induced by TGF-beta1 in cultured rat and human mesangial cells. HGF also inhibited TGF-beta1-mediated fibronectin and type I collagen expression. Such action of HGF was dependent on the activation of extracellular signal-regulated kinase-1 and -2 but not on Akt and p38 mitogen-activated protein kinase. HGF did not affect TGF-beta1-mediated Smad2 phosphorylation and its nuclear translocation. However, it rapidly upregulated Smad transcriptional corepressor TG-interacting factor (TGIF) abundance in mesangial cells, which was primarily mediated by stabilizing its protein from degradation. Ectopic expression of TGIF markedly suppressed Smad-mediated activation of TGF-beta1-responsive promoter activity and completely blocked TGF-beta1-induced a-smooth muscle actin expression. In vivo, TGIF expression was dramatically downregulated in the glomeruli of diabetic kidneys,,and delivery of exogenous HGF induced TGIF expression. These results suggest that HGF specifically antagonizes the profibrotic action of TGF-beta1 in mesangial cells by stabilizing Smad transcriptional corepressor TGIF.