Sodium and Potassium Balance Depends on αENaC Expression in Connecting Tubule

Mutations in alpha, beta, or gamma subunits of the epithelial sodium channel (ENaC) can downregulate ENaC activity and cause a severe salt-losing syndrome with hyperkalemia and metabolic acidosis, designated pseudohypoaldosteronism type 1 in humans In contrast, mice with selective inactivation of alpha ENaC in the collecting duct (CD) maintain sodium and potassium balance, suggesting that the late distal convoluted tubule (DCT2) and/or the connecting tubule (CNT) participates in sodium homeostasis To investigate the relative importance of ENaC mediated sodium absorption in the CNT we used Cre-lox technology to generate mice lacking alpha ENaC in the aquaporin 2 expressing CNT and CD Western blot analysis of microdissected cortical CD (CCD) and CNT revealed absence of alpha ENaC in the CCD and weak alpha ENaC expression in the CNT These mice exhibited a significantly higher urinary sodium excretion, a lower urine osmolality, and an increased urine volume compared with control mice Furthermore, serum sodium was lower and potassium levels were higher in the genetically modified mice With dietary sodium restriction these mice experienced significant weight loss, increased urinary sodium excretion, and hyperkalemia Plasma aldosterone levels were significantly elevated under both standard and sodium restricted diets In summary, alpha ENaC expression within the CNT/CD is crucial for sodium and potassium homeostasis and causes signs and symptoms of pseudohypoaldosteronism type 1 if missing