Regulation of Na+ transport by aldosterone: signaling convergence and cross talk between the PI3-K and MAPK1/2 cascades.
Regulation of Na+ transport by aldosterone: signaling convergence and cross talk between the PI3-K and MAPK1/2 cascades.
复制标题
醛固酮调节 Na 转运：PI3-K 和 MAPK1/2 级联之间的信号汇聚和串扰。
DOI：
10.1152/ajprenal.00345.2003
复制
发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Stockand,JamesD
中科院分区：
文献类型：
--
作者：
Tong,Qiusheng;Booth,RachellE;Worrell,RogerT;Stockand,JamesD
在肾 A6 上皮细胞中研究了磷脂酰肌醇 3-激酶 (PI3-K) 和丝裂原激活蛋白激酶 (MAPK)1/2 信号级联反应响应醛固酮诱导的 K-RasA 之间的串扰。此外，还研究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 A6 细胞中的活性 K-RasA 水平，导致 MAPK1/2 和 PI3-K 级联中下游效应器的激活，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 信号传导在 Akt 介导的 c-Raf 磷酸化水平（在已建立的负调控位点）上影响 MAPK1/2 级联。醛固酮还增加 Sgk 水平，并以 PI3-K 和 K-RasA 依赖性方式刺激该激酶的磷酸化。 MAPK1/2 信号传导的阻断对 Na+ 转运几乎没有影响。相反，抑制 PI3-K 会显着抑制转运。同样，抑制 K-RasA 诱导也会减少转运。然而，在这些条件下，Na+转运随后被 PLA2 抑制剂马兜铃酸（一种已确定的 Na+转运正调节剂）刺激，表明通过 PI3-K 的 K-RasA 信号传导并不直接影响上皮钠通道 (ENaC) 水平，而是影响该通道的活性。与这种可能性相一致的是，在中国仓鼠卵巢细胞中重建的ENaC活性通过共表达组成型活性PI3-K而增加。目前的研究表明，醛固酮部分通过刺激 PI3-K 信号传导来增加 Na+ 转运，并且在醛固酮作用期间，两种醛固酮诱导蛋白 K-RasA 和 Sgk 之间存在信号传导收敛，以及 PI3-K 和 MAPK1/2 级联之间的串扰，其中前级联（但不是后级联）增强 ENaC 活性。
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 PLA2inhibitor 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.