WNK4 regulates airway Na⁺ transport: Study of familial hyperkalaemia and hypertension

Background: WNK [With No K (lysine)] kinases are essential for regulation of blood pressure and potassium homeostasis. WNK4 expression was recently found not only in the distal nephron but also in chloride-transporting epithelia. To establish a physiological role for this distribution we studied patients with familial hyperkalaemia and hypertension (FHH), [pseudohypoaldosteronism type II (PHAII)], which is caused by mutations in WNK4. Design: Measurement of nasal potential difference (NPD) and sweat electrolytes were performed in controls, in six subjects with FHH and ten subjects with cystic fibrosis (CF). Results: Basal NPD was higher in FHH compared with controls (n = 20): 22.8 ± 5.7 vs. 16.2 ± 5.3 mV, respectively (P = 0.014). Maximal response to amiloride was also higher in FHH compared with controls: 14.8 ± 3.5 vs. 10.0 ± 4.8 mV, respectively (P = 0.03). In CF these values were 42.9 ± 9.3 and 29.9 ± 7.4 mV, respectively. The kinetics of the amiloride effect were faster in FHH, and as first reported here also in CF, compared with controls. At 30 s, amiloride-inhibitable residual PD in FHH was 50 ± 30 vs. 81 ± 9% in controls (P = 0.0003) and 56 ± 7% in CF. The response to chloride-free and isoproterenol solutions, which determines chloride transport activity, was similar in FHH compared with controls [16.0 ± 8.6 vs. 10.4 ± 5.9 mV (P = 0.08)]. Sweat conductivity in FHH was 49.7 ± 7.3 vs. 38.2 ± 8.1 mmol (NaCl eq) L^-1 in 16 controls (P = 0.007) and 94.0 ± 19.3 in CF. Conclusions: Mutant WNK4 increases Na⁺ transport in airways, and therefore it is regulated by wild-type WNK4. This may be caused by a regulation of ENaC or a K⁺ channel.