{Reference Type}: Journal Article
{Title}: Low potassium activation of proximal mTOR/AKT signaling is mediated by Kir4.2.
{Author}: Zhang Y;Bock F;Ferdaus M;Arroyo JP;L Rose K;Patel P;Denton JS;Delpire E;Weinstein AM;Zhang MZ;Harris RC;Terker AS;
{Journal}: Nat Commun
{Volume}: 15
{Issue}: 1
{Year}: 2024 Jun 17
{Factor}: 17.694
{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.