Mechanisms of angiotensin II signaling on cytoskeleton of podocytes
Mechanisms of angiotensin II signaling on cytoskeleton of podocytes
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DOI：
10.1007/s00109-008-0399-y
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发表时间：
2008-12-01
影响因子：
4.7
通讯作者：
Pavenstaedt, Hermann
中科院分区：
文献类型：
--
作者：
Hsu, Hsiang-Hao;Hoffmann, Sigrid;Pavenstaedt, Hermann
足细胞在建立肾小球滤过屏障中起着重要作用。肾素-血管紧张素系统(RAS)的持续激活在足细胞损伤和蛋白尿的发病机制中起着至关重要的作用。本研究表明，血管紧张素II(Ang II)可导致稳定表达血管紧张素II 1型受体(AT1R)的培养小鼠足细胞发生ROS依赖的F-肌动蛋白重排和迁移表型转换。激活的小GTP酶Rac-1和磷酸化的Ezrin/Radioxin/Moesin(ERM)蛋白可刺激Ang II诱导的F-肌动蛋白细胞骨架重构。这项工作还显示RAC-1和磷酸化ERM蛋白在培养的足细胞和足细胞特异性AT1R转基因大鼠(NEPH-hAT1 TGRS)的肾小球中表达增加。自由基清除剂DMTU可抑制Ang II诱导的细胞迁移、ERM蛋白磷酸化和皮质F-肌动蛋白重塑，表明ROS介导了Rac-1对足细胞AT1R信号的影响。肝素是一种有效的G偶联蛋白激酶2抑制剂，可阻断血管紧张素Ⅱ处理的足细胞ERM蛋白的磷酸化和皮质F-肌动蛋白环的形成，表明磷酸化的ERM蛋白是AT1R信号转导的细胞骨架效应器。此外，血管紧张素II刺激可下调α-肌动蛋白-4的表达，减少足细胞局部黏附的表达。Ang II处理的足细胞信号抑制实验表明，Rac-1、RhoA和F-肌动蛋白重组参与了AT1R信号转导中α-Actinin-4的表达调控。随着RAS的持续激活，Ang II诱导的表型从动态稳定转变为适应性迁移，最终可能耗尽足细胞，导致高肌动蛋白细胞骨架转换，导致足细胞枯竭和局灶性节段性肾小球硬化。
Podocytes are significant in establishing the glomerular filtration barrier. Sustained rennin-angiotensin system (RAS) activation is crucial in the pathogenesis of podocyte injury and causes proteinuria. This study demonstrates that angiotensin II (Ang II) caused a reactive oxygen species (ROS)-dependent rearrangement of cortical F-actin and a migratory phenotype switch in cultured mouse podocytes with stable Ang II type 1 receptor (AT1R) expression. Activated small GTPase Rac-1 and phosphorylated ezrin/radixin/moesin (ERM) proteins provoked Ang II-induced F-actin cytoskeletal remodeling. This work also shows increased expression of Rac-1 and phosphorylated ERM proteins in cultured podocytes, and in glomeruli of podocyte-specific AT1R transgenic rats (Neph-hAT1 TGRs). The free radical scavenger DMTU eliminated Ang II-induced cell migration, ERM protein phosphorylation and cortical F-actin remodeling, indicating that ROS mediates the influence of Rac-1 on podocyte AT1R signaling. Heparin, a potent G-coupled protein kinase 2 inhibitor, was found to abolish ERM protein phosphorylation and cortical F-actin ring formation in Ang II-treated podocytes, indicating that phosphorylated ERM proteins are the cytoskeletal effector in AT1R signaling. Moreover, Ang II stimulation triggered down-regulation of alpha actinin-4 and reduced focal adhesion expression in podocytes. Signaling inhibitor assay of Ang II-treated podocytes reveals that Rac-1, RhoA, and F-actin reorganization were involved in expressional regulation of alpha actinin-4 in AT1R signaling. With persistent RAS activation, the Ang II-induced phenotype shifts from being dynamically stable to adaptively migratory, which may eventually exhaust podocytes with a high actin cytoskeletal turnover, causing podocyte depletion and focal segmental glomerulosclerosis.