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 (TgWnk4^WT) and PHAII mutant (TgWnk4^PHAII) 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 (J_K) and the half-time to reach steady-state luminal K⁺ concentration (T_1/2) were measured under control-K⁺ (CK) and high-K⁺ (HK) dietary conditions. Quantitative PCR revealed reduced ROMK expression in TgWnk4^PHAII mice compared with wild-type mice. Micropuncture studies showed significantly reduced K⁺ secretion in the late distal tubule under CK conditions in TgWnk4^PHAII mice. Iberiotoxin had no effect on J_K or T_1/2 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 TgWnk4^PHAII mice is due to reduced ROMK-mediated transport and is not compensated by Maxi-K channels under normal K⁺ intake. The TgWnk4^PHAII 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.