Channelpedia

PubMed 25415435


Referenced in Channelpedia wiki pages of: none

Automatically associated channels: Kir1.1



Title: mTORC2 regulates renal tubule sodium uptake by promoting ENaC activity.

Authors: Catherine E Gleason, Gustavo Frindt, Chih-Jen Cheng, Michael Ng, Atif Kidwai, Priyanka Rashmi, Florian Lang, Michel Baum, Lawrence G Palmer, David Pearce

Journal, date & volume: J. Clin. Invest., 2015 Jan , 125, 117-28

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/25415435


Abstract
The epithelial Na+ channel (ENaC) is essential for Na+ homeostasis, and dysregulation of this channel underlies many forms of hypertension. Recent studies suggest that mTOR regulates phosphorylation and activation of serum/glucocorticoid regulated kinase 1 (SGK1), which is known to inhibit ENaC internalization and degradation; however, it is not clear whether mTOR contributes to the regulation of renal tubule ion transport. Here, we evaluated the effect of selective mTOR inhibitors on kidney tubule Na+ and K+ transport in WT and Sgk1-/- mice, as well as in isolated collecting tubules. We found that 2 structurally distinct competitive inhibitors (PP242 and AZD8055), both of which prevent all mTOR-dependent phosphorylation, including that of SGK1, caused substantial natriuresis, but not kaliuresis, in WT mice, which indicates that mTOR preferentially influences ENaC function. PP242 also substantially inhibited Na+ currents in isolated perfused cortical collecting tubules. Accordingly, patch clamp studies on cortical tubule apical membranes revealed that mTOR inhibition markedly reduces ENaC activity, but does not alter activity of K+ inwardly rectifying channels (ROMK channels). Together, these results demonstrate that mTOR regulates kidney tubule ion handling and suggest that mTOR regulates Na+ homeostasis through SGK1-dependent modulation of ENaC activity.