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 9

Model of Na+ and K+ transport regulation by local and systemic [K+] in PCs of the CCD.

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Model of Na+ and K+ transport regulation by local and systemic [K+] in P...
Cellular model of the integrated regulation of ENaC activity, and ENaC-dependent K+ secretion, in response to altered plasma K+. Green arrows indicate stimulatory effects. Red arrow indicates inhibitory effect. Solid arrows indicate rapid direct effects (seconds to minutes), dashed arrows indicate slower genomic effects (minutes to hours). According to this scheme, elevation of basolateral [K+] triggers membrane depolarization by altering the K+ channel–dominated resting potential, which with a possible involvement of intracellular [Cl–] and WNK1 stimulates mTORC2-dependent SGK1 activation via HM phosphorylation. Activated SGK1 stimulates ENaC predominately by inhibiting Nedd4-2, but also potentially through other effects including ENaC phosphorylation. The ensuing increase in electrogenic Na+ transport enhances K+ secretion via K+ channels, predominantly renal outer medullary K+ (ROMK) channels, but also large-conductance Ca2-activated K+ (BK) channels. According to the model, SGK1 acts as a signal integrator, responding both to local signals that increase its activity, and to systemic hormonal signals (primarily aldosterone), which increase its expression.