1. Low potassium activation of proximal mTOR/AKT signaling is mediated by Kir4.2.
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Zhang, Yahua, Bock, Fabian, Ferdaus, Mohammed, Arroyo, Juan Pablo, L Rose, Kristie, Patel, Purvi, Denton, Jerod S., Delpire, Eric, Weinstein, Alan M., Zhang, Ming-Zhi, Harris, Raymond C., and Terker, Andrew S.
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PROXIMAL kidney tubules ,POTASSIUM channels ,POTASSIUM ,THREE-dimensional imaging ,SIGNALS & signaling ,EPITHELIAL cells ,CELL growth - 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. The renal epithelium is sensitive to changes in blood K+ . Here, Zhang et al. identify low K+ as a potent activator of proximal tubule mTOR/AKT signaling, which occurs through the K+ channel, Kir4.2 to modulate epithelial cell growth and Na+ transport. [ABSTRACT FROM AUTHOR]- Published
- 2024
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