Rho-kinase mediates TNF-α-induced MCP-1 expression via p38 MAPK signaling pathway in mesangial cells
Rho-kinase mediates TNF-α-induced MCP-1 expression via p38 MAPK signaling pathway in mesangial cells
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DOI：
10.1016/j.bbrc.2010.10.093
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发表时间：
2010-11-26
影响因子：
3.1
通讯作者：
Utsunomiya, Kazunori
中科院分区：
文献类型：
--
作者：
Matoba, Keiichiro;Kawanami, Daiji;Utsunomiya, Kazunori
单核细胞趋化蛋白-1 （MCP-1）在募集单核细胞到肾小球的过程中起着核心作用。肿瘤坏死因子- α (tnf - α)已被证明可诱导肾小球系膜细胞中MCP-1的表达，尽管其确切机制尚不清楚。我们之前已经证明RhoA及其效应物rho激酶（rho相关的含螺旋状线圈的蛋白激酶ROCK）参与了炎症性肾小球疾病的发生在本研究中，我们研究了Rho/Rho激酶信号通路是否调节TNF- α介导的MCP-1在系膜细胞中的诱导作用，小鼠系膜细胞（MES-13）暴露于TNF- α导致MCP-1表达（通过RT-PCR）和分泌到培养基中（通过ELISA）基于这些观察，我们推测Rho/Rho激酶信号通路可能参与了tnf - α诱导MCP-1的过程，与这一概念一致，Y-27632一种特异性的Rho激酶抑制剂减弱了tnf - α介导的MCP-1的诱导。我们证明Y-27632抑制了tnf - α介导的单核细胞迁移和减弱了tnf - α介导的p38 MAPK的激活。基于这些数据，我们推断Y-27632抑制了tnf - α诱导的MCP-1的表达分泌和我们的研究表明，Rho/Rho激酶是炎症性肾病肾小球内单核细胞募集和积聚的重要治疗靶点(C) 2010 Elsevier Inc . All rights reserved
Macrophage accumulation has been implicated in the pathogenesis of Inflammatory glomerular disease Monocyte chemoattractant protein-1 (MCP-1) plays a central role in recruiting monocytes to the glomeruli Tumor necrosis factor-alpha (TNF-alpha) has been shown to Induce MCP-1 expression in mesangial cells although the precise mechanisms remain unclear We previously demonstrated that RhoA and its effector Rho-kinase (Rho-associated coiled-coil containing protein kinase ROCK) are involved in the pathogenesis of diabetic nephropathy However its role in MCP-1 induction by TNF-alpha has not been elucidated In the present study we investigated whether the Rho/Rho-kinase signaling pathway regulates the TNF alpha-mediated induction of MCP-1 in mesangial cells Exposure of mouse mesangial cells (MES-13) to TNF-alpha resulted in an increase of MCP-1 expression (by RT-PCR) and secretion into the medium (by ELISA) Pull down and Western blot analysis revealed that TNF-alpha activated RhoA and Rho-kinase Based on these observations we speculated that the Rho/Rho-kinase signaling pathway may be involved in MCP-1 induction by TNF-alpha In agreement with this concept Y-27632 a specific Rho-kinase inhibitor attenuated TNF-alpha-mediated induction of MCP-1 We demonstrated that Y-27632 inhibited TNF-alpha-mediated monocyte migration and attenuated TNF-alpha-mediated p38 MAPK activation Based on these data we Infer that Y-27632 inhibits TNF-alpha-induced MCP-1 expression secretion and function through inhibition of Rho-kinase and p38 MAPK activity Our study suggests that Rho/Rho-kinase is an important therapeutic target of monocyte recruitment and accumulation within the glomerulus in inflammatory renal disease (C) 2010 Elsevier Inc All rights reserved