Mechanisms of Renal Control of Potassium Homeostasis in Complete Aldosterone Deficiency

Aldosterone-independent mechanisms may contribute to K⁺ homeostasis. We studied aldosterone synthase knockout (AS^−/−) mice to define renal control mechanisms of K⁺ homeostasis in complete aldosterone deficiency. AS^−/− mice were normokalemic and tolerated a physiologic dietary K⁺ load (2% K⁺, 2 days) without signs of illness, except some degree of polyuria. With supraphysiologic K⁺ intake (5% K⁺), AS^−/− mice decompensated and became hyperkalemic. High-K⁺ diets induced upregulation of the renal outer medullary K⁺ channel in AS^−/− mice, whereas upregulation of the epithelial sodium channel (ENaC) sufficient to increase the electrochemical driving force for K⁺ excretion was detected only with a 2% K⁺ diet. Phosphorylation of the thiazide-sensitive NaCl cotransporter was consistently lower in AS^−/− mice than in AS^+/+ mice and was downregulated in mice of both genotypes in response to increased K⁺ intake. Inhibition of the angiotensin II type 1 receptor reduced renal creatinine clearance and apical ENaC localization, and caused severe hyperkalemia in AS^−/− mice. In contrast with the kidney, the distal colon of AS^−/− mice did not respond to dietary K⁺ loading, as indicated by Ussing-type chamber experiments. Thus, renal adaptation to a physiologic, but not supraphysiologic, K⁺ load can be achieved in aldosterone deficiency by aldosterone-independent activation of the renal outer medullary K⁺ channel and ENaC, to which angiotensin II may contribute. Enhanced urinary flow and reduced activity of the thiazide-sensitive NaCl cotransporter may support renal adaptation by activation of flow-dependent K⁺ secretion and increased intratubular availability of Na⁺ that can be reabsorbed in exchange for K⁺ secreted.