SGK integrates insulin and mineralocorticoid regulation of epithelial sodium transport.
SGK integrates insulin and mineralocorticoid regulation of epithelial sodium transport.
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DOI：
10.1152/ajprenal.2001.280.2.f303
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发表时间：
2001-02
期刊：
影响因子：
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通讯作者：
Jian Wang;P. Barbry;A. C. Maiyar;D. Rozansky;A. Bhargava;M. Leong;G. Firestone;D. Pearce
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文献类型：
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作者：
Jian Wang;P. Barbry;A. C. Maiyar;D. Rozansky;A. Bhargava;M. Leong;G. Firestone;D. Pearce
上皮Na+通道(ENaC)是Na+跨紧致上皮细胞转运的限速步骤，是激素调节的主要靶点，尤其是胰岛素和糖皮质激素的调节。最近，丝氨酸苏氨酸激酶(SGK)被发现是一种快速的盐皮质激素反应基因，其产物刺激ENaC介导的Na+转运。与其近亲蛋白激酶B(也称为Akt)一样，SGK的激酶活性依赖于磷脂酰肌醇3-激酶(PI3K)，磷脂酰肌醇3-激酶是胰岛素信号的关键中介。在我们的研究中，我们证明PI3K是SGK依赖的刺激ENaC介导的Na+转运以及产生磷酸化的SGK所必需的。在A6肾细胞中，盐皮质激素对磷酸化的SGK的诱导先于Na+转运的增加，而PI3K的特异性抑制既抑制了SGK的磷酸化又抑制了盐皮质激素诱导的Na+转运。胰岛素可增强SGK的磷酸化，并与盐皮质激素协同刺激Na+转运。在非洲爪哇卵母细胞共表达实验中，SGK刺激的ENaC活性也被PI3K抑制显著降低。最后，体外翻译的SGK与在大肠杆菌中表达的ENaC亚基以谷胱甘肽S-转移酶融合蛋白的形式特异性地相互作用。这些数据表明，SGK是依赖于PI3K的胰岛素和盐皮质激素作用的整合者，它与ENaC亚基相互作用，控制Na+进入肾脏集合管细胞。
The epithelial Na+ channel (ENaC) constitutes the rate-limiting step for Na+ transport across tight epithelia and is the principal target of hormonal regulation, particularly by insulin and mineralocorticoids. Recently, the serine-threonine kinase (SGK) was identified as a rapidly mineralocorticoid-responsive gene, the product of which stimulates ENaC-mediated Na+ transport. Like its close relative, protein kinase B (also called Akt), SGK's kinase activity is dependent on phosphatidylinositol 3-kinase (PI3K), a key mediator of insulin signaling. In our study we show that PI3K is required for SGK-dependent stimulation of ENaC-mediated Na+ transport as well as for the production of the phosphorylated form of SGK. In A6 kidney cells, mineralocorticoid induction of the phosphorylated form of SGK preceded the increase in Na+ transport, and specific inhibition of PI3K inhibited both phosphorylation of SGK and mineralocorticoid-induced Na+ transport. Insulin both augmented SGK phosphorylation and synergized with mineralocorticoids in stimulating Na+ transport. In a Xenopus laevis oocyte coexpression assay, SGK-stimulated ENaC activity was also markedly reduced by PI3K inhibition. Finally, in vitro-translated SGK specifically interacted with the ENaC subunits expressed in Escherichia coli as glutathione S-transferase fusion proteins. These data suggest that SGK is a PI3K-dependent integrator of insulin and mineralocorticoid actions that interacts with ENaC subunits to control Na+ entry into kidney collecting duct cells.