Hypertension of Kcnmb1⁻/⁻ is linked to deficient K secretion and aldosteronism

• Published in: Proceedings of the National Academy of Sciences - PNAS 2009, Vol.106 (28), p.11800-11805
• Main Authors: Grimm, P. Richard, Irsik, Debra L, Settles, Deann C, Holtzclaw, J. David, Sansom, Steven.C
• Format: Article
• Language: English
• Subjects: antagonists; diet; genes; hyperkalemia; hypertension; mice; mineralocorticoid receptors; phenotype; potassium; potassium channels; secretion; smooth muscle; sodium
• ISSN: 0027-8424; 1091-6490

Mice lacking the β1-subunit (gene, Kcnmb1; protein, BK-β1) of the large Ca-activated K channel (BK) are hypertensive. This phenotype is thought to result from diminished BK currents in vascular smooth muscle where BK-β1 is an ancillary subunit. However, the β1-subunit is also expressed in the renal connecting tubule (CNT), a segment of the aldosterone-sensitive distal nephron, where it associates with BK and facilitates K secretion. Because of the correlation between certain forms of hypertension and renal defects, particularly in the distal nephron, it was determined whether the hypertension of Kcnmb1⁻/⁻ has a renal origin. We found that Kcnmb1⁻/⁻ are hypertensive, volume expanded, and have reduced urinary K and Na clearances. These conditions are exacerbated when the animals are fed a high K diet (5% K; HK). Supplementing HK-fed Kcnmb1⁻/⁻ with eplerenone (mineralocorticoid receptor antagonist) corrected the fluid imbalance and more than 70% of the hypertension. Finally, plasma [aldo] was elevated in Kcnmb1⁻/⁻ under basal conditions (control diet, 0.6% K) and increased significantly more than wild type when fed the HK diet. We conclude that the majority of the hypertension of Kcnmb1⁻/⁻ is due to aldosteronism, resulting from renal potassium retention and hyperkalemia.