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

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.