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This Article Full Text Full Text (PDF) All Versions of this Article: 295/3/F843    most recent 90348.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Wang, J. Articles by Pearce, D. PubMed PubMed Citation Articles by Wang, J. Articles by Pearce, D.

Activity of the p110- subunit of phosphatidylinositol-3-kinase is required for activation of epithelial sodium transport

¹Division of Nephrology, Department of Medicine, San Francisco General Hospital, and ²Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California

Submitted 5 June 2008 ; accepted in final form 17 July 2008

The pathways implicated in the control of epithelial Na⁺ channel (ENaC)-dependent Na⁺ transport in renal collecting duct cells share substantial parallels with those implicated in insulin-regulated glucose metabolism. Notably, both are inhibited by wortmannin and LY294002 and signal through phosphatidylinositol-3-kinase (PI3K)-dependent kinases SGK1 and Akt. The inhibitor pattern is thought to reflect dependence on PI3K activity since wortmannin and LY294002 are both effective inhibitors of this kinase. However, these inhibitors block a variety of kinases from different families and lack specificity within the PI3K family. To begin to dissect more precisely the pathways required for signaling and for control of Na⁺ transport in renal collecting duct cells, we have examined the effect of a set of PI3K inhibitors, which selectively block distinct subsets of PI3K catalytic subunit isoforms. We have found that ENaC-dependent Na⁺ transport was blocked by inhibitors of the p110- isoform of PI3K, but not by inhibitors of p110-β, -, or -. Inhibitors that block Na⁺ current also blocked SGK1 and Akt phosphorylation. In contrast to insulin-stimulated glucose uptake in muscle cells, p110-β inhibition did not enhance sensitivity to p110- inhibition. These data support the conclusion that ENaC-dependent Na⁺ current is controlled exclusively by p110-, the same isoform that is the principal mediator of insulin effects on glucose metabolism, and lacks any dependence on p110-β. These findings further underscore the extent to which Na⁺ and glucose regulation are intertwined and provide additional insight into the interconnections between diabetes and hypertension.

phosphoinositide; sgk; phosphatidylinositol-3-phosphokinase; insulin; aldosterone