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Acute Regulation of the Epithelial Na⁺ Channel by Phosphatidylinositide 3-OH Kinase Signaling in Native Collecting Duct Principal Cells

Alexander Staruschenko^*, Oleh Pochynyuk^*, Alain Vandewalle, Vladislav Bugaj^* and James D. Stockand^*

^* University of Texas Health Science Center, Department of Physiology, San Antonio, Texas; and INSERM, U773, Centre de Recherche Biomedicale Bichat-Beaujon CRB3, and Universite Paris 7, Denis Diderot, site Bichat, Paris, France

Address correspondence to: Dr. James D. Stockand, University of Texas Health Science Center, Department of Physiology, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900. Phone: 210-567-4332; Fax: 210-567-4410; E-mail: stockand{at}uthscsa.edu

Received for publication January 5, 2007. Accepted for publication March 7, 2007.

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)P₃, 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)P₃ levels, demonstrating tight spatiotemporal coupling between ENaC activity and PI3-K/PI(3,4,5)P₃ 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.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673