Reduced Renal K + Excretion With Compensatory Hyperaldosteronism In K Ca 1.1 Channel β 2 ‐subunit KO Mice

The kidneys are the primary organs responsible for excreting K + , ensuring whole body K + homeostasis by precisely matching K + excretion to dietary K + intake. K + is secreted into the urine in the collecting ducts, and two distinct mechanisms for K + secretion exist; a constitutive mechanism mediated by ROMK (Kir1.1) in principal cells and a flow‐induced mechanism mediated by BK channels (K Ca 1.1) in intercalated cells. Both mechanisms are up‐regulated by aldosterone. Here we studied renal K + excretion in KO mice for the β 2 ‐subunit of the BK channel. The β 2 KO mice have increased plasma aldosterone, low renin expression and normal plasma [K + ]. The low renin in β 2 KO mice indicates that hyperaldosteronism was triggered by a K + handling deficiency, rather than hypotension and activation of the renin‐angiotensin‐aldosterone system. We hypothesize that β 2 KO mice have decreased BK channel‐mediated renal K + secretion, which is compensated by hyperaldosteronism and up‐regulation of ROMK‐mediated K + secretion, allowing β 2 KO mice to maintain normal plasma [K + ]. In fact, when treated with eplerenone (mineralocorticoid receptor antagonist) for 4 days, β 2 KO mice develop slight hyperkalemia (4.15 mM ± 0.13 in WT vs. 4.60 mM ± 0.10 in KO, P = 0.013). Urinary K + excretion following oral K + load (20% of normal daily intake) was not different between WT and KO mice under control conditions. However, when treated with eplerenone, β 2 KO mice had a significantly lower urinary K + excretion rate (P=0.044) and significantly higher plasma [K + ] 3 hours after oral K + load (10.0 mM ± 0.4 in WT vs. 11.4 mM ± 0.5 in KO, P = 0.044). Our data support that hyperaldosteronism in β 2 KO mice is part of a chronic compensation to a decreased BK channel‐mediated renal K + secretion. Supported by the Lundbeck foundation.