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 Ca(2+)-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.

Na+ dependence of K+‐induced natriuresis, kaliuresis and Na+/Cl− cotransporter dephosphorylation

“…, Larsen et al . ). However, the mechanisms inducing diuresis in our two experimental conditions may be different.…”

Potassium acts through mTOR to regulate its own secretion

“…The control gavage only contained glucose. The mice received a volume of 20 μl/g BW and a total K + load that corresponds to approximately 25% of daily K + intake (53). Gavage was always given at 9 am and urine was collected as spot urine during the following 4 hours.…”

Intact colonic KCa1.1 channel activity in KCNMB2 knockout mice

“…All expression assays have been verified on positive expressing tissues in a previous publication from our group (Larsen et al. ).…”

“…Mice were genotyped as described previously (Larsen et al. ). The LRRC26 strain was generated in the C57BL/6NTac background by KOMP, Davis, CA.…”