[HTML][HTML] mTORC2 regulates renal tubule sodium uptake by promoting ENaC activity

CE Gleason, G Frindt, CJ Cheng, M Ng… - The Journal of …, 2015 - Am Soc Clin Investig
CE Gleason, G Frindt, CJ Cheng, M Ng, A Kidwai, P Rashmi, F Lang, M Baum, LG Palmer…
The Journal of clinical investigation, 2015Am Soc Clin Investig
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 …
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.
The Journal of Clinical Investigation