Mechanism of impaired potassium transport in pseudohypoaldosteronism (type II).

Pseudohypoaldosteronism type II (PHAII), also known as Gordon syndrome, is an autosomal-dominant disorder caused by mutations in with-no-lysine kinase 4 (WNK4) and is characterized by increased renal sodium chloride (NaCl) reabsorption and impaired potassium (K+) secretion. We examined the relative contributions of renal outer medullary K+ (ROMK) channels and large-conductance Ca2+-activated K+ (BK; Maxi-K) channels to distal K+ secretion in wild-type (TgWnk4WT) and PHAII mutant (TgWnk4PHAII) mice. Renal clearance and stationery microperfusion techniques were used to assess urinary Na+ and K+ excretion and K+ secretion in the late distal tubule. Potassium secretion (JK) and the half-time to reach steady-state luminal K+ concentration (T1/2) were measured under control-K+ (CK) and high-K+ (HK) dietary conditions. Quantitative PCR revealed reduced ROMK expression in TgWnk4PHAII mice compared with wild-type mice. Micropuncture studies showed significantly reduced K+ secretion in the late distal tubule under CK conditions in TgWnk4PHAII mice. Iberiotoxin had no effect on JK or T1/2 in either genotype under CK conditions. In contrast, HK feeding increased distal K+ secretion in both genotypes, and this increase was completely abolished by iberiotoxin. These findings indicate that impaired K+ secretion in TgWnk4PHAII mice is due to reduced ROMK-mediated transport and is not compensated by Maxi-K channels under normal K+ intake. The TgWnk4PHAII mutation does not impair HK-stimulated Maxi-K channel-mediated K+ secretion in the distal nephron.NEW & NOTEWORTHY Our findings demonstrate that PHAII-associated WNK4 mutations impair ROMK-dependent distal K+ secretion while preserving high-K+-stimulated Maxi-K channel function, thereby revealing distinct contributions of these channels to renal K+ homeostasis.