mTORC2 regulates renal tubule sodium uptake by promoting ENaC activity

作者：Gleason Catherine E; Frindt Gustavo; Cheng Chih Jen; Ng Michael; Kidwai Atif; Rashmi Priyanka; Lang Florian; Baum Michel; Palmer Lawrence G; Pearce David^*

来源：Journal of Clinical Investigation, 2015, 125(1): 117-128.

DOI：10.1172/JCI73935

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.

• 出版日期2015-1