Low potassium activation of proximal mTOR/AKT signaling is mediated by Kir4.2

Yahua Zhang, Fabian Bock, Mohammed Ferdaus, Juan Pablo Arroyo, Kristie L Rose, Purvi Patel, Jerod S. Denton, Eric Delpire, Alan M. Weinstein, Ming-Zhi Zhang, Raymond C. Harris and Andrew S. Terker ()
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Yahua Zhang: Vanderbilt University Medical Center
Fabian Bock: Vanderbilt University Medical Center
Mohammed Ferdaus: Vanderbilt University Medical Center
Juan Pablo Arroyo: Vanderbilt University Medical Center
Kristie L Rose: Vanderbilt University School of Medicine
Purvi Patel: Vanderbilt University School of Medicine
Jerod S. Denton: Vanderbilt University Medical Center
Eric Delpire: Vanderbilt University Medical Center
Alan M. Weinstein: Weil Medical College
Ming-Zhi Zhang: Vanderbilt University Medical Center
Raymond C. Harris: Vanderbilt University Medical Center
Andrew S. Terker: Vanderbilt University Medical Center

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract The renal epithelium is sensitive to changes in blood potassium (K+). We identify the basolateral K+ channel, Kir4.2, as a mediator of the proximal tubule response to K+ deficiency. Mice lacking Kir4.2 have a compensated baseline phenotype whereby they increase their distal transport burden to maintain homeostasis. Upon dietary K+ depletion, knockout animals decompensate as evidenced by increased urinary K+ excretion and development of a proximal renal tubular acidosis. Potassium wasting is not proximal in origin but is caused by higher ENaC activity and depends upon increased distal sodium delivery. Three-dimensional imaging reveals Kir4.2 knockouts fail to undergo proximal tubule expansion, while the distal convoluted tubule response is exaggerated. AKT signaling mediates the dietary K+ response, which is blunted in Kir4.2 knockouts. Lastly, we demonstrate in isolated tubules that AKT phosphorylation in response to low K+ depends upon mTORC2 activation by secondary changes in Cl- transport. Data support a proximal role for cell Cl- which, as it does along the distal nephron, responds to K+ changes to activate kinase signaling.

Date: 2024
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DOI: 10.1038/s41467-024-49562-w

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