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1 Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
2 Department of Chemistry and Biochemistry, Texas State University, Cincinnati, OH, USA
3 Department of Surgery, University of Cincinnati, San Marcos, TX, USA
* To whom correspondence should be addressed. E-mail: rbooth{at}txstate.edu.
Cross-talk between the PI3-K and MAPK1/2 signaling cascades in response to aldosterone-induced K-RasA was investigated in renal A6 epithelial cells. The contribution of these signaling pathways to aldosterone-stimulated Na+ transport, in addition, was investigated. Aldosterone increased active K-RasA levels in A6 cells resulting in activation of downstream effectors in both the MAPK 1/2 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 upon the MAPK 1/2 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 MAPK 1/2 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 ENaC levels but activity of this channel. Consistent with this possibility, activity of ENaC reconstituted in CHO cells was increased by co-expression 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 MAPK 1/2 cascades with the prior but not latter cascade enhancing ENaC activity.
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