Hyperaldosteronism after decreased renal K+ excretion in KCNMB2 knockout mice

Abstract

The kidney is the primary organ ensuring K+ homeostasis. K+ is secreted into the urine in the distal tubule by two mechanisms: by the renal outer medullary K+ channel (Kir1.1) and by the Ca2+-activated K+ channel (KCa1.1). Here, we report a novel knockout mouse of the β2-subunit of the KCa1.1 channel (KCNMB2), which displays hyperaldosteronism after decreased renal K+ excretion. KCNMB2−/− mice displayed hyperaldosteronism, normal plasma K+ concentration, and produced dilute urine with decreased K+ concentration. The normokalemia indicated that hyperaldosteronism did not result from primary aldosteronism. Activation of the renin-angiotensin-aldosterone system was also ruled out as renal renin mRNA expression was reduced in KCNMB2−/− mice. Renal K+ excretion rates were similar in the two genotypes; however, KCNMB2−/− mice required elevated plasma aldosterone to achieve K+ balance. Blockade of the mineralocorticoid receptor with eplerenone triggered mild hyperkalemia and unmasked reduced renal K+ excretion in KCNMB2−/− mice. Knockout mice for the α-subunit of the KCa1.1 channel (KCNMA1−/− mice) have hyperaldosteronism, are hypertensive, and lack flow-induced K+ secretion. KCNMB2−/− mice share the phenotypic traits of normokalemia and hyperaldosteronism with KCNMA1−/− mice but were normotensive and displayed intact flow-induced K+ secretion. Despite elevated plasma aldosterone, KNCMB2−/− mice did not display salt-sensitive hypertension and were able to decrease plasma aldosterone on a high-Na+ diet, although plasma aldosterone remained elevated in KCNMB2−/− mice. In summary, KCNMB2−/− mice have a reduced ability to excrete K+ into the urine but achieve K+ balance through an aldosterone-mediated, β2-independent mechanism. The phenotype of KCNMB2 mice was similar but milder than the phenotype of KCNMA1−/− mice.