Potassium acts through mTOR to regulate its own secretion
Mads Vaarby Sørensen, Bidisha Saha, Iben Skov Jensen, Peng Wu, Niklas Ayasse, Catherine E. Gleason, Samuel Levi Svendsen, Wen-Hui Wang, David Pearce
Mads Vaarby Sørensen, Bidisha Saha, Iben Skov Jensen, Peng Wu, Niklas Ayasse, Catherine E. Gleason, Samuel Levi Svendsen, Wen-Hui Wang, David Pearce
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Research Article Cell biology Nephrology

Potassium acts through mTOR to regulate its own secretion

Abstract

Potassium (K+) secretion by kidney tubule cells is central to electrolyte homeostasis in mammals. In the K+-secreting principal cells of the distal nephron, electrogenic Na+ transport by the epithelial sodium channel (ENaC) generates the electrical driving force for K+ transport across the apical membrane. Regulation of this process is attributable in part to aldosterone, which stimulates the gene transcription of the ENaC-regulatory kinase, SGK1. However, a wide range of evidence supports the conclusion that an unidentified aldosterone-independent pathway exists. We show here that in principal cells, K+ itself acts through the type 2 mTOR complex (mTORC2) to activate SGK1, which stimulates ENaC to enhance K+ excretion. The effect depends on changes in K+ concentration on the blood side of the cells, and requires basolateral membrane K+-channel activity. However, it does not depend on changes in aldosterone, or on enhanced distal delivery of Na+ from upstream nephron segments. These data strongly support the idea that K+ is sensed directly by principal cells to stimulate its own secretion by activating the mTORC2/SGK1 signaling module, and stimulate ENaC. We propose that this local effect acts in concert with aldosterone and increased Na+ delivery from upstream nephron segments to sustain K+ homeostasis.

Authors

Mads Vaarby Sørensen, Bidisha Saha, Iben Skov Jensen, Peng Wu, Niklas Ayasse, Catherine E. Gleason, Samuel Levi Svendsen, Wen-Hui Wang, David Pearce

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Figure 8

Role of WNK1 in extracellular [K+]–stimulated phosphorylation of SGK1.

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Role of WNK1 in extracellular [K+]–stimulated phosphorylation of SGK1. (...
(A) Western blot analyses showing effects of WT (aa 1–491) versus kinase-dead WNK1 mutant (aa 1–491) (K233M) on extracellular [K+]–stimulated phosphorylation of SGK1. WNK1-deficient HEK-293 cells were transfected with FLAG-SGK1 and WNK1 (aa 1–491) WT or (aa 1–491) K233M. Cells were adapted to 1 mM [K+], and then media [K+] was either raised to 5 mM or kept at 1 mM for 1 hour. In cells lacking WT or WNK1 K233M, raising extracellular [K+] to 5 mM failed to stimulate SGK1 phosphorylation. Cells expressing K233M exhibited higher abundance of p-SGK1 compared with cells expressing WT WNK1. (B) Quantification of the Western blot data, presented as mean ± SEM from 3 independent experiments. **P < 0.01, ****P < 0.0001 by 1-way ANOVA. NS, not significant.