title: Activity of the p110-alpha subunit of phosphatidylinositol-3-kinase is required for activation of epithelial sodium transport.
abstract: 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-alpha isoform of PI3K, but not by inhibitors of p110-beta, -gamma, or -delta. Inhibitors that block Na(+) current also blocked SGK1 and Akt phosphorylation. In contrast to insulin-stimulated glucose uptake in muscle cells, p110-beta inhibition did not enhance sensitivity to p110-alpha inhibition. These data support the conclusion that ENaC-dependent Na(+) current is controlled exclusively by p110-alpha, the same isoform that is the principal mediator of insulin effects on glucose metabolism, and lacks any dependence on p110-beta. 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.
authors.affiliation: Division of Nephrology, Department of Medicine, San Francisco General Hospital, 1001 Potrero Avenue, San Francisco, CA 94110, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Knight
authors.forename: Dorothea
authors.initials: D
authors.lastname: Fiedler
authors.forename: Olusegun
authors.initials: O
authors.lastname: Williams
authors.forename: Kevan M
authors.initials: KM
authors.lastname: Shokat
authors.forename: David
authors.initials: D
authors.lastname: Pearce
mesh_terms: D000818:Animals; D002460:Cell Line; D058534:Class I Phosphatidylinositol 3-Kinases; D004847:Epithelial Cells / Q000378:metabolism*; D053503:Epithelial Sodium Channels / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D017874:Immediate-Early Proteins / Q000378:metabolism; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D053503:Epithelial Sodium Channels; D005947:Glucose; D017874:Immediate-Early Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D012964:Sodium; D000099184:Serum-Glucocorticoid Regulated Kinases; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse