Yang Junwei, Dai Chunsun, Liu Youhua
Division of Cellular and Molecular Pathology, Department of Pathology, University of Pittsburgh School of Medicine, S-405 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15261, USA.
J Am Soc Nephrol. 2005 Jan;16(1):68-78. doi: 10.1681/ASN.2003090795. Epub 2004 Nov 10.
Hepatocyte growth factor (HGF) is a potent antifibrotic cytokine that blocks tubular epithelial to mesenchymal transition (EMT) induced by TGF-beta1. However, the underlying mechanism remains largely unknown. This study investigated the signaling events that lead to HGF blockade of the TGF-beta1-initiated EMT. Incubation of human kidney epithelial cells HKC with HGF only marginally affected the expression of TGF-beta1 and its type I and type II receptors, suggesting that disruption of TGF-beta1 signaling likely plays a critical role in mediating HGF inhibition of TGF-beta1 action. However, HGF neither affected TGF-beta1-induced Smad-2 phosphorylation and its subsequent nuclear translocation nor influenced the expression of inhibitory Smad-6 and -7 in tubular epithelial cells. HGF specifically induced the expression of Smad transcriptional co-repressor SnoN but not Ski and TG-interacting factor at both mRNA and protein levels in HKC cells. SnoN physically interacted with activated Smad-2 by forming transcriptionally inactive complex and overrode the profibrotic action of TGF-beta1. In vivo, HGF did not affect Smad-2 activation and its nuclear accumulation in tubular epithelium, but it restored SnoN protein abundance in the fibrotic kidney in obstructive nephropathy. Hence, HGF blocks EMT by antagonizing TGF-beta1's action via upregulating Smad transcriptional co-repressor SnoN expression. These findings not only identify a novel mode of interaction between the signals activated by HGF receptor tyrosine kinase and TGF-beta receptor serine/threonine kinases but also illustrate the feasibility of confining Smad activity as an effective strategy for blocking renal fibrosis.
肝细胞生长因子（HGF）是一种强效抗纤维化细胞因子，可阻断由转化生长因子-β1（TGF-β1）诱导的肾小管上皮细胞向间充质细胞转化（EMT）。然而，其潜在机制在很大程度上仍不清楚。本研究调查了导致HGF阻断TGF-β1启动的EMT的信号事件。用人肾上皮细胞HKC与HGF孵育仅轻微影响TGF-β1及其I型和II型受体的表达，这表明TGF-β1信号的破坏可能在介导HGF对TGF-β1作用的抑制中起关键作用。然而，HGF既不影响TGF-β1诱导的Smad-2磷酸化及其随后的核转位，也不影响肾小管上皮细胞中抑制性Smad-6和-7的表达。HGF在HKC细胞的mRNA和蛋白质水平上特异性诱导Smad转录共抑制因子SnoN的表达，但不诱导Ski和TG相互作用因子的表达。SnoN通过形成转录无活性复合物与活化的Smad-2发生物理相互作用，并克服了TGF-β1的促纤维化作用。在体内，HGF不影响肾小管上皮中Smad-2的激活及其核积累，但它恢复了梗阻性肾病纤维化肾脏中SnoN蛋白的丰度。因此，HGF通过上调Smad转录共抑制因子SnoN的表达来拮抗TGF-β1的作用，从而阻断EMT。这些发现不仅确定了HGF受体酪氨酸激酶激活的信号与TGF-β受体丝氨酸/苏氨酸激酶激活的信号之间的一种新的相互作用模式，而且还说明了限制Smad活性作为阻断肾纤维化的有效策略的可行性。
