Mediation of Na‐independent K secretion by intercalated cell BK‐α/β4

Abstract

In the classic mode of K secretion, K is exchanged for reabsorbing Na in the distal nephron. However, Paleolithic humans consumed an alkaline diet of low Na, high K content, indicating a mechanism of Na independent K secretion. We used BK-β4 knock-out mice (β4KO) to test the hypothesis that BK-α/β4 channels, localized in intercalated cells, are utilized to secrete K with HCO3 in a Na-independent manner. We found that the plasma [K] of wild type mice (WT) increased from a normal diet (0.32%Na + 0.6%K) value of 4.02 to a value of 4.33 when placed on a low Na (0.01%), normal K, diet for 10 days. However, plasma [K] of β4KO increased from 4.05 to 4.75 on a low Na diet, a value significantly greater than WT, consistent with a defect in Na-independent K secretion. We then treated WT and β4KO with a normal Na, high K (5%K with equal amounts of Cl, citrate, and carbonate) diet for 10 days and administered the ENaC inhibitor amiloride (5 mg/kg/day via osmotic pump) for the last two days. We found that urinary [Na] to plasma [Na] (UNa/PNa) increased similarly, by approximately 2-fold, in both WT and β4KO treated with amiloride. However, the urine [K] to plasma [K] ratio (UK/PK) of β4KO was 27.0, a value significantly lower than WT (74.5). These results indicate that BK-β4 has a role in a Na-independent mode of K secretion.