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

  • Nat Commun. 2024 Jun 17;15(1):5144. doi: 10.1038/s41467-024-49562-w.
Yahua Zhang  1  2 ,  Fabian Bock  1  2 ,  Mohammed Ferdaus  3 ,  Juan Pablo Arroyo  1  2 ,  Kristie L Rose  4  5 ,  Purvi Patel  5 ,  Jerod S Denton  3 ,  Eric Delpire  3 ,  Alan M Weinstein  6 ,  Ming-Zhi Zhang  1  2 ,  Raymond C Harris  1  2  7 ,  Andrew S Terker  8  9
Affiliations
  • 1. Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 2. Vanderbilt Center for Kidney Disease, Nashville, TN, USA.
  • 3. Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 4. Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA.
  • 5. Mass Spectrometry Research Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
  • 6. Department of Physiology and Biophysics, Weil Medical College, New York, NY, USA.
  • 7. Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA.
  • 8. Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. [email protected].
  • 9. Vanderbilt Center for Kidney Disease, Nashville, TN, USA. [email protected].
PMID: 38886379 DOI: 10.1038/s41467-024-49562-w
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.

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