Journal article
mTORC2 regulates renal tubule sodium uptake by promoting ENaC activity
The Journal of clinical investigation, Vol.125(1), pp.117-128
01/01/2015
DOI: 10.1172/JCI73935
PMCID: PMC4382226
PMID: 25415435
Abstract
The epithelial Na+ channel (ENaC) is essential for Na+ homeostasis, and dysregulation of this channel underlies mariy 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.
Details
- Title: Subtitle
- mTORC2 regulates renal tubule sodium uptake by promoting ENaC activity
- Creators
- Catherine E. Gleason - University of California, San FranciscoGustavo Frindt - Cornell UniversityChih-Jen Cheng - The University of Texas Southwestern Medical CenterMichael Ng - University of California, San FranciscoAtif Kidwai - Tufts UniversityPriyanka Rashmi - University of California, San FranciscoFlorian Lang - University of TübingenMichel Baum - The University of Texas Southwestern Medical CenterLawrence G. Palmer - Cornell UniversityDavid Pearce - University of California, San Francisco
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.125(1), pp.117-128
- DOI
- 10.1172/JCI73935
- PMID
- 25415435
- PMCID
- PMC4382226
- NLM abbreviation
- J Clin Invest
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Publisher
- Amer Soc Clinical Investigation Inc
- Number of pages
- 12
- Grant note
- P3ODK 079328; DK59659 / O'Brien Center DK56695; T32 DK007219; K01 DK098313-02; DK41612; DK078596 / National Institutes of Diabetes and Digestive and Kidney Diseases; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) PP242 / James Hilton Manning and Emma Austin Manning Foundation T32DK007219 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK)
- Language
- English
- Date published
- 01/01/2015
- Academic Unit
- Nephrology; Internal Medicine
- Record Identifier
- 9984383303502771
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