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.