Hepatocyte growth factor suppresses renal interstitial myofibroblast activation and intercepts Smad signal transduction
Hepatocyte growth factor suppresses renal interstitial myofibroblast activation and intercepts Smad signal transduction
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DOI：
10.1016/s0002-9440(10)63689-9
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发表时间：
2003-08-01
影响因子：
6
通讯作者：
Liu, YH
中科院分区：
文献类型：
--
作者：
Yang, JW;Dai, CS;Liu, YH
间质肌成纤维细胞是α-平滑肌肌动蛋白阳性细胞，在肾间质纤维化过程中过量细胞外基质的积累中起关键作用。尽管它们在肾纤维化的发病机制中的重要性，但对疾病条件下控制肾间质肌成纤维细胞活化的调节剂和机制知之甚少。在这里，我们表明，肝细胞生长因子（HGF）作为一个有效的抑制剂转化生长因子（TGF）-β 1介导的成肌纤维细胞激活正常大鼠肾间质成纤维细胞（NRK-49 F）。同时孵育HGF以剂量依赖性方式消除TGF-β 1诱导的新生α-平滑肌肌动蛋白表达、F-肌动蛋白重组和间质胶原I过度产生。为了解释HGF拮抗TGF-β 1作用的机制，我们研究了HGF对TGF-β 1介导的Smad信号传导的影响。HGF既不抑制TGF-β 1诱导的Smad-2/3磷酸化及其与Smad-4的结合，也不显著影响NRK-49 F细胞中抑制性Smad-6和-7表达以及Smad转录辅阻遏物的细胞丰度。然而，HGF预处理显著减弱了活化的Smad-2/3核转位和积聚。HGF的这种作用显然依赖于HGF介导的细胞外信号调节激酶-1和-2（Erk-1/2）的磷酸化和激活。Mek激酶抑制剂PD 98059抑制Erk-1/2活化可恢复TGF-β 1诱导的Smad-2/3核积聚和肌成纤维细胞活化。在体内，HGF选择性地阻断Smad-2/3核在单侧输尿管梗阻诱导的纤维化肾脏中的肾间质细胞中的积聚。因此，HGF抑制TGF-β 1介导的肾间质成肌纤维细胞活化;并且HGF的这种作用可能与丝裂原活化蛋白激酶依赖性阻断Smad核转位有关。
Interstitial myofibroblasts are a-smooth muscle actin-positive cells that play a crucial role in the accumulation of excess extracellular matrix during renal interstitial fibrogenesis. Despite their importance in the pathogenesis of renal fibrosis, relatively little is known about the regulators and the mechanism controlling the activation of renal interstitial myofibroblasts in disease conditions. Here, we show that hepatocyte growth factor (HGF) acts as a potent inhibitor of the transforming growth factor (TGF)-beta1-mediated myofibroblastic activation from normal rat renal interstitial fibroblasts (NRK-49F). Simultaneous incubation of HGF abolished TGF-beta1-induced de novo a-smooth muscle actin expression, F-actin reorganization, and interstitial collagen I overproduction in a dose-dependent manner. To decipher the mechanism underlying HGF antagonizing TGF-beta1's action, we examined the effects of HGF on TGF-beta1-mediated Smad signaling. HGF neither inhibited Smad-2/3 phosphorylation and their association with Smad-4 induced by TGF-beta1, nor significantly affected inhibitory Smad-6 and -7 expression and cellular abundance of Smad transcriptional co-repressors in NRK-49F cells. However, pretreatment with HGF markedly attenuated activated Smad-2/3 nuclear translocation and accumulation. This action of HGF was apparently dependent on HGF-mediated extracellular signal-regulated kinase-1 and -2 (Erk-1/2) phosphorylation and activation. Inhibition of Erk-1/2 activation by Mek kinase inhibitor PD98059 restored TGF-beta1-inediated Smad-2/3 nuclear accumulation and myofibroblast activation. In vivo, HGF selectively blocked Smad-2/3 nuclear accumulation in renal interstitial cells in the fibrotic kidneys induced by unilateral ureteral obstruction Therefore, HGF suppresses TGF-beta1-mediated renal interstitial myofibroblastic activation; and this action of HGF is likely related to a mitogen-activated protein kinase-dependent blockade of Smad nuclear translocation.