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

PR Grimm, DL Irsik, DC Settles… - Proceedings of the …, 2009 - National Acad Sciences
PR Grimm, DL Irsik, DC Settles, JD Holtzclaw, SC Sansom
Proceedings of the National Academy of Sciences, 2009National Acad Sciences
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 …
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.
National Acad Sciences