Role of Rho GDP dissociation inhibitor α in control of epithelial sodium channel (ENaC)-mediated sodium reabsorption.
Role of Rho GDP dissociation inhibitor α in control of epithelial sodium channel (ENaC)-mediated sodium reabsorption.
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Rho GDP 解离抑制剂 α 在控制上皮钠通道 (ENaC) 介导的钠重吸收中的作用。
DOI：
10.1074/jbc.m114.558262
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Staruschenko,Alexander
中科院分区：
文献类型：
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作者：
Pavlov,TengisS;Levchenko,Vladislav;Staruschenko,Alexander
上皮钠通道（ENaC）在醛固酮敏感的远端肾单位中表达，在那里它执行来自管腔的钠重吸收。我们最近发现，由于EGF水平不足，ENaC活性有助于盐诱发高血压的发展。已有研究表明Rho GDP解离抑制因子α（RhoGDIα）通过Rac 1参与盐敏感性高血压和肾损伤的调控，Rac 1是激活ENaC的小GTP酶之一。我们研究了RhoGDIα/Rac 1轴参与ENaC调控的细胞内机制以及EGF对ENaC的影响。我们证明RhoGDIα在小鼠和大鼠的皮质集合管中高度表达，并且其表达在喂食高盐饮食的Dahl盐敏感大鼠中下调。在培养的皮质集合管主细胞中敲低RhoGDIα增加ENaC亚基表达和ENaC介导的钠重吸收。此外，RhoGDIα缺乏导致对EGF治疗的反应增强。膜片钳分析表明，RhoGDIα显着降低ENaC电流密度，并阻止其由RhoA和Rac 1上调。用Y27632抑制Rho激酶对对照或RhoGDIα敲低细胞中ENaC对EGF的反应没有影响。然而，EGF处理增加了活性Rac 1的水平，这在RhoGDIα缺陷细胞中进一步增强。我们的结论是，RhoGDIα依赖性通路的变化在Rac 1介导的盐诱导高血压中观察到的ENaC活性增强中具有允许的作用。
The epithelial sodium channel (ENaC) is expressed in the aldosterone-sensitive distal nephron where it performs sodium reabsorption from the lumen. We have recently shown that ENaC activity contributes to the development of salt-induced hypertension as a result of deficiency of EGF level. Previous studies revealed that Rho GDP-dissociation inhibitor α (RhoGDIα) is involved in the control of salt-sensitive hypertension and renal injury via Rac1, which is one of the small GTPases activating ENaC. Here we investigated the intracellular mechanism mediating the involvement of the RhoGDIα/Rac1 axis in the control of ENaC and the effect of EGF on ENaC in this pathway. We demonstrated that RhoGDIα is highly expressed in the cortical collecting ducts of mice and rats, and its expression is down-regulated in Dahl salt-sensitive rats fed a high salt diet. Knockdown of RhoGDIα in cultured cortical collecting duct principal cells increased ENaC subunits expression and ENaC-mediated sodium reabsorption. Furthermore, RhoGDIα deficiency causes enhanced response to EGF treatment. Patch clamp analysis reveals that RhoGDIα significantly decreases ENaC current density and prevents its up-regulation by RhoA and Rac1. Inhibition of Rho kinase with Y27632 had no effects on ENaC response to EGF either in control or RhoGDIα knocked down cells. However, EGF treatment increased levels of active Rac1, which was further enhanced in RhoGDIα-deficient cells. We conclude that changes in the RhoGDIα-dependent pathway have a permissive role in the Rac1-mediated enhancement of ENaC activity observed in salt-induced hypertension.