L-WNK1 is required for BK channel activation in intercalated cells

Abstract

BK channels expressed in intercalated cells (ICs) in the aldosterone-sensitive distal nephron (ASDN) mediate flow-induced K⁺ secretion. In the ASDN of mice and rabbits, IC BK channel expression and activity increase with a high K⁺ diet. In cell culture, the long isoform of the kinase WNK1 (L-WNK1) increases BK channel expression and activity. Apical L-WNK1 expression is selectively enhanced in ICs in the ASDN of rabbits on a high K⁺ diet, suggesting that L-WNK1 contributes to BK channel regulation by dietary K⁺. We examined the role of IC L-WNK1 expression in enhancing BK channel activity in response to a high K⁺ diet. Mice with an IC-selective deletion of L-WNK1 (IC-L-WNK1-KO) and littermate controls were placed on a high K⁺ (5% K⁺ as KCl) diet for 10 or more days. IC-L-WNK1-KO mice exhibited reduced IC apical/subapical BK α subunit expression and BK channel-dependent whole-cell currents compared to controls. Six-hour urinary K⁺ excretion in response a saline load was similar in IC-L-WNK1-KO mice and controls. The observations that IC-L-WNK1-KO mice on a high K⁺ diet have higher blood [K⁺] and reduced IC BK channel activity are consistent with impaired urinary K⁺ secretion, demonstrating that IC L-WNK1 has a role in the renal adaptation to a high K⁺ diet.