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首页> 外文期刊>American Journal of Physiology >Regulation of Na+ transport by aldosterone: signaling convergence and cross talk between the PI3-K and MAPK1/2 cascades.
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Regulation of Na+ transport by aldosterone: signaling convergence and cross talk between the PI3-K and MAPK1/2 cascades.

机译：醛固酮对Na +转运的调节：指示PI3-K和MAPK1 / 2级联之间的收敛和串扰。

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Cross talk between the phosphatidylinositol 3-kinase (PI3-K) and mitogen-activating protein kinase (MAPK)1/2 signaling cascades in response to aldosterone-induced K-RasA was investigated in renal A6 epithelial cells. In addition, the contribution of these signaling pathways to aldosterone-stimulated Na(+) transport was investigated. Aldosterone increased active K-RasA levels in A6 cells resulting in activation of downstream effectors in both the MAPK1/2 and PI3-K cascades with K-RasA directly interacting with the catalytic p110 subunit of PI3-K in a steroid-dependent manner. Aldosterone-stimulated PI3-K signaling impinged on the MAPK1/2 cascade at the level of Akt-mediated phosphorylation of c-Raf at an established negative regulatory site. Aldosterone also increased Sgk levels as well as stimulated phosphorylation of this kinase in a PI3-K- and K-RasA-dependent manner. Blockade of MAPK1/2 signaling had little effect on Na(+) transport. Conversely, inhibition of PI3-K markedly suppressed transport. Likewise, suppression of K-RasA induction decreased transport. However, Na(+) transport was subsequently stimulated under these conditions with the PLA(2) inhibitor aristolochic acid, an established positive modulator of Na(+) transport, suggesting that K-RasA signaling through PI3-K does not directly affect epithelial sodium channel (ENaC) levels but the activity of this channel. Consistent with this possibility, activity of ENaC reconstituted in Chinese hamster ovary cells was increased by coexpression of constitutively active PI3-K. The current study demonstrates that aldosterone increases Na(+) transport, in part, by stimulating PI3-K signaling and that during aldosterone actions, there is both signaling convergence between the two aldosterone-induced proteins, K-RasA and Sgk, as well as cross talk between the PI3-K and MAPK1/2 cascades with the prior but not latter cascade enhancing ENaC activity.
机译：在肾A6上皮细胞中研究了磷脂酰肌醇3激酶（PI3-K）和促分裂原活化蛋白激酶（MAPK）1/2信号级联反应对醛固酮诱导的K-RasA的串扰。此外，调查了这些信号通路对醛固酮刺激的Na（+）转运的贡献。醛固酮增加了A6细胞的活性K-RasA水平，导致MAPK1 / 2和PI3-K级联中下游效应子的激活，其中K-RasA以类固醇依赖性方式直接与PI3-K的催化p110亚基相互作用。醛固酮刺激的PI3-K信号以既定的负调控位点Akt介导的c-Raf磷酸化水平撞击MAPK1 / 2级联。醛固酮还以PI3-K-和K-RasA-依赖性方式增加了Sgk水平并刺激了该激酶的磷酸化。 MAPK1 / 2信号的封锁对Na（+）转运影响很小。相反，对PI3-K的抑制显着抑制了转运。同样，抑制K-RasA诱导减少了运输。但是，随后在这些条件下用PLA（2）抑制剂马兜铃酸刺激了Na（+）转运，后者是Na（+）转运的已建立的正调节剂，表明通过PI3-K的K-RasA信号传导不会直接影响上皮钠通道（ENaC）级别，但该通道的活动。与这种可能性一致，在中国仓鼠卵巢细胞中重构的ENaC活性通过组成型活性PI3-K的共表达而增加。当前的研究表明，醛固酮部分地通过刺激PI3-K信号传导来增加Na（+）转运，并且在醛固酮的作用过程中，两种醛固酮诱导的蛋白质K-RasA和Sgk以及两者之间都存在信号衔接。 PI3-K和MAPK1 / 2级联之间的串扰与先前但不是后来的级联增强ENaC活性有关。

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