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Aldosterone and ENaC: From Genetics to Physiology

Regulation of Na⁺ transport by aldosterone: signaling convergence and cross talk between the PI3-K and MAPK1/2 cascades

¹Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio 78229-3900; ²Department of Chemistry and Biochemistry, Texas State University, San Marcos, Texas 78666; and ³Epithelial Pathobiology Group, Department of Surgery, University of Cincinnati, Cincinnati, Ohio 45219

Submitted 26 September 2003 ; accepted in final form 18 February 2004

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 PLA₂ 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.

epithelial sodium channel; downstream effectors; Ras; serum and glucocorticoid-induced kinase; hypertension

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