title: 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.
authors.affiliation: Department of Biomedicine, Physiology, and Health, Aarhus University, Aarhus, Denmark;
authors.forename: Casper K
authors.initials: CK
authors.lastname: Larsen
authors.affiliation: Department of Biomedicine, Physiology, and Health, Aarhus University, Aarhus, Denmark;
authors.forename: Iben S
authors.initials: IS
authors.lastname: Jensen
authors.affiliation: Department of Biomedicine, Physiology, and Health, Aarhus University, Aarhus, Denmark; Aarhus Institute for Advanced Studies, Aarhus University, Aarhus, Denmark; and.
authors.forename: Mads V
authors.initials: MV
authors.lastname: Sorensen
authors.affiliation: Department of Biomedicine, Physiology, and Health, Aarhus University, Aarhus, Denmark;
authors.forename: Pauline I
authors.initials: PI
authors.lastname: de Bruijn
authors.affiliation: Institute of Physiology, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Bleich
authors.affiliation: Department of Biomedicine, Physiology, and Health, Aarhus University, Aarhus, Denmark;
authors.forename: Helle A
authors.initials: HA
authors.lastname: Praetorius
authors.affiliation: Department of Biomedicine, Physiology, and Health, Aarhus University, Aarhus, Denmark; leip@biomed.au.dk.
authors.forename: Jens
authors.initials: J
authors.lastname: Leipziger
mesh_terms: D000450:Aldosterone / Q000097:blood; D000818:Animals; D001794:Blood Pressure; D053503:Epithelial Sodium Channels / Q000378:metabolism; D000077545:Eplerenone; D005260:Female; D006929:Hyperaldosteronism / Q000209:etiology*; D007668:Kidney / Q000378:metabolism*; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits / Q000172:deficiency*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011141:Polyuria / Q000209:etiology; D011188:Potassium / Q000652:urine*; D012982:Sodium, Dietary / Q000008:administration & dosage; D064486:Solute Carrier Family 12, Member 3 / Q000378:metabolism; D013148:Spironolactone / Q000031:analogs & derivatives
chemical_list: D053503:Epithelial Sodium Channels; C000609143:Kcnmb2 protein, mouse; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits; D012982:Sodium, Dietary; D064486:Solute Carrier Family 12, Member 3; D013148:Spironolactone; D000450:Aldosterone; D000077545:Eplerenone; D011188:Potassium
keywords: KCa1.1 channel; potassium excretion; α-subunit of the KCa1.1 channel; β2-subunit