Faculty Collaboration Database

Acute regulation of the epithelial Na+ channel by phosphatidylinositide 3-OH kinase signaling in native collecting duct principal cells. J Am Soc Nephrol 2007 Jun;18(6):1652-61

Date

04/20/2007

Pubmed ID

17442787

DOI

10.1681/ASN.2007010020

Scopus ID

2-s2.0-34249863860 (requires institutional sign-in at Scopus site)   82 Citations

Abstract

Activity of the epithelial Na(+) channel (ENaC) is limiting for Na(+) reabsorption in the aldosterone-sensitive distal nephron. Hormones, including aldosterone and insulin, increase ENaC activity, in part by stimulating phosphatidylinositide 3-OH kinase (PI3-K) signaling. Recent studies in heterologous expression systems reveal a close spatiotemporal coupling between PI3-K signaling and ENaC activity with the phospholipid product of this kinase, PI(3,4,5)P(3), in some cases, directly binding the channel and increasing open probability (P(o)). This study tested whether this tight coupling plays a physiologic role in modulating ENaC activity in native tissue and polarized epithelial cells. IGF-I was found to increase Na(+) reabsorption across mpkCCD(c14) principal cell monolayers in a PI3-K-sensitive manner. Inhibition of PI3-K signaling, moreover, rapidly decreased Na(+) reabsorption and ENaC activity in mpkCCD(c14) cells that were treated with corticosteroids and IGF-I. These decreases paralleled changes in apical membrane PI(3,4,5)P(3) levels, demonstrating tight spatiotemporal coupling between ENaC activity and PI3-K/PI(3,4,5)P(3) signaling within this membrane. For further probing of the mechanism underpinning this coupling, cortical collecting ducts (CCD) were isolated from rat and split open to expose the apical membrane for patch-clamp analysis. Inhibition of PI3-K signaling with wortmannin and LY294002 but not its inactive analogue rapidly and markedly decreased the P(o) of ENaC. Moreover, IGF-I acutely increased P(o) of ENaC in CCD principal cells in a PI3-K-sensitive manner. Together, these observations stress the importance of tight spatiotemporal coupling between PI3-K signaling and ENaC within the apical membrane of principal cells to the physiologic control of this ion channel.

Author List

Staruschenko A, Pochynyuk O, Vandewalle A, Bugaj V, Stockand JD

MESH terms used to index this publication - Major topics in bold

Androstadienes
Animals
Cell Line, Transformed
Cell Polarity
Chromones
Enzyme Inhibitors
Epithelial Sodium Channels
Female
Insulin-Like Growth Factor I
Kidney Tubules, Collecting
Male
Mice
Morpholines
Patch-Clamp Techniques
Phosphatidylinositol 3-Kinases
Phosphatidylinositols
Protein Kinase Inhibitors
Rats
Rats, Sprague-Dawley
Signal Transduction
Sodium
Tight Junctions