Oncostatin M-induced effects on EMT in human proximal tubular cells:: differential role of ERK signaling
Oncostatin M-induced effects on EMT in human proximal tubular cells:: differential role of ERK signaling
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DOI：
10.1152/ajprenal.00130.2007
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发表时间：
2007-11-01
影响因子：
4.2
通讯作者：
Schramek, Herbert
中科院分区：
文献类型：
--
作者：
Pollack, Verena;Sarkoezi, Rita;Schramek, Herbert
越来越多的证据表明，在肾小管间质纤维化过程中检测到的间质肌成纤维细胞的比例来源于肾小管上皮细胞通过称为上皮间质转化（EMT）的过程。IL-6型细胞因子抑瘤素M（OSM）最近已被牵连在诱导EMT。我们研究了OSM对细胞-细胞接触蛋白和间充质标志物表达的影响，并研究了OSM诱导的与人类近端肾小管细胞中这些事件相关的细胞内信号传导机制。人重组OSM减弱了人肾-2（HK-2）细胞中N-钙粘蛋白、E-钙粘蛋白和claudin-2的表达，这与诱导HK-2细胞在3D胶原基质中分散有关。相反，OSM诱导I型胶原、波形蛋白和S100 A4的表达。抗gp 130抗体可抑制OSM刺激的细胞散射。除了诱导Stat 1和Stat 3的磷酸化外，OSM还导致促分裂原活化蛋白激酶ERK 1、ERK 2和ERK 5的强烈浓度和时间依赖性磷酸化。MEK 1/2抑制剂U 0126（10 μ M）阻断基础和OSM诱导的ERK 1/2磷酸化，但不阻断ERK 5或Stat 1/3的磷酸化。当以抑制ERK 1/2磷酸化但不抑制ERK 5磷酸化的浓度使用时，合成的MEK 1/2抑制剂U 0126和Cl-1040都在OSM存在下恢复N-钙粘蛋白表达，抑制基础密蛋白-2表达，但不影响基础或OSM抑制的E-钙粘蛋白表达或OSM诱导的I型胶原和波形蛋白表达。这些结果表明，在人类近端肾小管细胞ERK 1/2信号是一个重要组成部分的OSM的抑制作用N-钙粘蛋白的表达。此外，功能性ERK 1/2信号传导对于基础claudin-2表达是必需的。
Growing evidence suggests that a proportion of interstitial myofibroblasts detected during renal tubulointerstitial fibrosis originates from tubular epithelial cells by a process called epithelial-mesenchymal transition (EMT). The IL-6-type cytokine oncostatin M (OSM) has been recently implicated in the induction of EMT. We investigated OSM effects on the expression of both cell-cell contact proteins and mesenchymal markers and studied OSM-induced intracellular signaling mechanisms associated with these events in human proximal tubular cells. Human recombinant OSM attenuated the expression of N-cadherin, E-cadherin, and claudin-2 in human kidney-2 (HK-2) cells associated with the induction of HK-2 cell scattering in 3D collagen matrices. Conversely, expression of collagen type I, vimentin, and S100A4 was induced by OSM. OSM-stimulated cell scattering was inhibited by antibodies against gp130. Besides inducing phosphorylation of Stat1 and Stat3, OSM led to a strong concentrationand time-dependent phosphorylation of the mitogen-activated protein kinases ERK1, ERK2, and ERK5. MEK1/2 inhibitor U0126 (10 mu M) blocked basal and OSM-induced ERK1/2 phosphorylation but not phosphorylation of either ERK5 or Stat1/3. Both synthetic MEK1/2 inhibitors U0126 and Cl-1040, when used at concentrations which inhibit ERK1/2 phosphorylation but not ERK5 phosphorylation, restored N-cadherin expression in the presence of OSM, inhibited basal claudin-2 expression, but did not affect either basal or OSM-inhibited E-cadherin expression or OSM-induced expression of collagen type I and vimentin. These results suggest that in human proximal tubular cells ERK1/2 signaling represents an important component of OSM's inhibitory effect on N-cadherin expression. Furthermore, functional ERK1/2 signaling is necessary for basal claudin-2 expression.