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

Area of Science:

• Nephrology
• Molecular Biology
• Physiology

Background:

• Large-conductance K+ (BK) channels in kidney intercalated cells (ICs) regulate potassium secretion.
• Dietary potassium intake influences BK channel expression and activity in the aldosterone-sensitive distal nephron (ASDN).
• The long isoform of with-no-lysine kinase 1 (L-WNK1) is implicated in regulating BK channels, with increased expression in ICs on high-potassium diets.

Purpose of the Study:

• To investigate the role of IC L-WNK1 in mediating the adaptive response of BK channels to a high-potassium diet.
• To determine if L-WNK1 in ICs is essential for regulating BK channel activity and potassium homeostasis during high potassium intake.

Main Methods:

• Generation of mice with IC-selective deletion of L-WNK1 (IC-L-WNK1-KO).
• Feeding control and IC-L-WNK1-KO mice a high-potassium diet (5% KCl) for at least 10 days.
• Assessment of IC BK channel subunit expression, whole-cell currents, urinary potassium excretion, and blood potassium concentration.

Main Results:

• IC-L-WNK1-KO mice showed reduced expression of BK channel alpha-subunits in the apical/subapical regions of ICs.
• BK channel-dependent whole-cell currents were blunted in ICs of IC-L-WNK1-KO mice on a high-potassium diet.
• Despite similar urinary potassium excretion after saline load, IC-L-WNK1-KO mice exhibited higher blood potassium concentrations, indicating impaired renal adaptation.

Conclusions:

• IC L-WNK1 plays a critical role in the renal adaptation to a high-potassium diet.
• L-WNK1 in ICs is necessary for maintaining normal BK channel activity and localization in response to increased dietary potassium.
• Disruption of IC L-WNK1 leads to impaired potassium handling and elevated blood potassium levels under high-potassium conditions.