MTORC2 regulates renal tubule sodium uptake by promoting ENaC activity

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

Research output: Contribution to journalArticle

27 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)117-128
Number of pages12
JournalJournal of Clinical Investigation
Volume125
Issue number1
DOIs
StatePublished - Jan 2 2015

ASJC Scopus subject areas

  • Medicine(all)

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    Gleason, C. E., Frindt, G., Cheng, C. J., Ng, M., Kidwai, A., Rashmi, P., Lang, F., Baum, M., Palmer, L. G., & Pearce, D. (2015). MTORC2 regulates renal tubule sodium uptake by promoting ENaC activity. Journal of Clinical Investigation, 125(1), 117-128. https://doi.org/10.1172/JCI73935