Aldosterone-dependent and -independent regulation of Na + and K + excretion and ENaC in mouse kidneys.

We investigated the regulation of Na ⁺ and K ⁺ excretion and the epithelial Na ⁺ channel (ENaC) in mice lacking the gene for aldosterone synthase (AS) using clearance methods to assess excretion and electrophysiology and Western blot analysis to test for ENaC activity and processing. After 1 day of dietary Na ⁺ restriction, AS ^-/- mice lost more Na ⁺ in the urine than AS ^+/+ mice did. After 1 wk on this diet, both genotypes strongly reduced urinary Na ⁺ excretion, but creatinine clearance decreased only in AS ^-/- mice. Only AS ^+/+ animals exhibited increased ENaC function, assessed as amiloride-sensitive whole cell currents in collecting ducts or cleavage of αENaC and γENaC in Western blots. To assess the role of aldosterone in the excretion of a K ⁺ load, animals were fasted overnight and refed with high-K ⁺ or low-K ⁺ diets for 5 h. Both AS ^+/+ and AS ^-/- mice excreted a large amount of K ⁺ during this period. In both phenotypes the excretion was benzamil sensitive, indicating increased K ⁺ secretion coupled to ENaC-dependent Na ⁺ reabsorption. However, the increase in plasma K ⁺ under these conditions was much larger in AS ^-/- animals than in AS ^+/+ animals. In both groups, cleavage of αENaC and γENaC increased. However, Na ⁺ current measured ex vivo in connecting tubules was enhanced only in AS ^+/+ mice. We conclude that in the absence of aldosterone, mice can conserve Na ⁺ without ENaC activation but at the expense of diminished glomerular filtration rate. Excretion of a K ⁺ load can be accomplished through aldosterone-independent upregulation of ENaC, but aldosterone is required to excrete the excess K ⁺ without hyperkalemia.