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

Large-conductance K⁺ (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 with-no-lysine kinase 1 (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 IC-selective deletion of L-WNK1 (IC-L-WNK1-KO) and littermate control mice 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 α-subunit expression and BK channel-dependent whole cell currents compared with 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⁺ concentration 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.NEW & NOTEWORTHY When mice are placed on a high-K⁺ diet, genetic disruption of the long form of with no lysine kinase 1 (L-WNK1) in intercalated cells reduced relative apical + subapical localization of the large-conductance K⁺ channel, blunted large-conductance K⁺ channel currents in intercalated cells, and increased blood K⁺ concentration. These data confirm an in vivo role of L-WNK1 in intercalated cells in adaptation to a high-K⁺ diet.