Role of collecting duct principal cell NOS1β in sodium and potassium homeostasis

The nitric oxide (NO)‐generating enzyme, NO synthase‐1β (NOS1β), is essential for sodium (Na + ) homeostasis and blood pressure control. We previously showed that collecting duct principal cell NOS1β is critical for inhibition of the epithelial sodium channel (ENaC) during high Na + intake. Previous studies on freshly isolated cortical collecting ducts (CCD) demonstrated that exogenous NO promotes basolateral potassium (K + ) conductance through basolateral channels, presumably K ir 4.1 ( Kcnj10) and K ir 5.1 ( Kcnj16 ). We, therefore, investigated the effects of NOS1β knockout on K ir 4.1/K ir 5.1 channel activity. Indeed, in CHO cells overexpressing NOS1β and K ir 4.1/K ir 5.1, the inhibition of NO signaling decreased channel activity. Male littermate control and principal cell NOS1β knockout mice (CDNOS1KO) on a 7‐day, 4% NaCl diet (HSD) were used to detect changes in basolateral K + conductance. We previously demonstrated that CDNOS1KO mice have high circulating aldosterone despite a high‐salt diet and appropriately suppressed renin. We observed greater K ir 4.1 cortical abundance and significantly greater K ir 4.1/K ir 5.1 single‐channel activity in the principal cells from CDNOS1KO mice. Moreover, blocking aldosterone action with in vivo spironolactone treatment resulted in lower K ir 4.1 abundance and greater plasma K + in the CDNOS1KO mice compared to controls. Lowering K + content in the HSD prevented the high aldosterone and greater plasma Na + of CDNOS1KO mice and normalized K ir 4.1 abundance. We conclude that during chronic HSD, lack of NOS1β leads to increased plasma K + , enhanced circulating aldosterone, and activation of ENaC and K ir 4.1/K ir 5.1 channels. Thus, principal cell NOS1β is required for the regulation of both Na + and K + by the kidney.