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JCI Insight. 2019 Apr 23;5. pii: 126910. doi: 10.1172/jci.insight.126910.

Potassium acts through mTOR to regulate its own secretion.

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Departments of Biomedicine and Physiology, Aarhus University, Aarhus, Denmark.
Aarhus Institute for Advanced Studies, Aarhus University, Aarhus, Denmark.
Department of Medicine, Division of Nephrology, and Department of Cellular and Molecular Pharmacology, UCSF, San Francisco, California, USA.
Department of Pharmacology, New York Medical College, Valhalla, New York, USA.


Potassium (K+) secretion by kidney tubule cells is central to electrolyte homeostasis in mammals. In the K+ secretory "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.


Cell Biology; Homeostasis; Nephrology; Signal transduction; Sodium channels

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