Potassium acts through mTOR to regulate its own secretion
Mads Vaarby Sørensen, … , Wen-Hui Wang, David Pearce
Mads Vaarby Sørensen, … , Wen-Hui Wang, David Pearce
Published April 23, 2019
Citation Information: JCI Insight. 2019;4(11):e126910. https://doi.org/10.1172/jci.insight.126910.
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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 4

SGK1 activity is required for K+ stimulation of ENaC.

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SGK1 activity is required for K+ stimulation of ENaC. (A and B) K+ stimu...
(A and B) K+ stimulates SGK1 phosphorylation in mpkCCD cells. Cells from Figure 3, B and C, were lysed and prepared for Western blot, and stained with antibodies as indicated. Upper panels: Western blot images showing blots stained with anti–phospho-SGK1 S422, total SGK1, and α-tubulin as labeled. Lower panels: Quantitation of phospho-SGK1/total SGK1 (as described in Methods). Data are mean ± SEM from 3 independent experiments. *P < 0.05, ***P < 0.001 by 1-way ANOVA (A, lower panel). NS, not significant. *P < 0.05 by 2-tailed Student’s t test (B, lower panel). (C and D) Inhibition of SGK1 activity decreases K+-induced ENaC activity. mpkCCD cells were adapted to 1 mM (C) or 3 mM (D) extracellular [K+] as in Figure 3, B and C. The SGK1 inhibitor GSK650394 or vehicle was added and extracellular [K+] was then increased by addition of KCl for 1 hour prior to determining amiloride-sensitive Na+ current. Data are mean ± SEM from 3 independent experiments. ***P < 0.001, ****P < 0.0001 by 1-way ANOVA. μA, microamperes.