A mutation in WNK4 that causes human hypertension activates the epithelial Na + channel in vivo

Mutations in the kinase WNK4 cause an inherited form of human hypertension, pseudohypoaldosteronism type II (PHAII). WNK4 has been shown to regulate the activity of several mediators of renal NaCl and K + flux. We now show by experiments in Xenopus oocytes and in mice with PHAII‐mutant WNK4 that WNK4 regulates the epithelial Na + channel (ENaC), a major effector of aldosterone signaling. In oocytes, WNK4 inhibits ENaC activity, as measured by amiloride‐sensitive whole cell currents (>50%, p< 2 x 10 −7 ), via a kinase‐independent mechanism that requires C‐termini of the channel’s β and γ subunits. A PHAII‐causing mutation in WNK4 abolishes this inhibition. SGK1, a known aldosterone‐stimulated activator of ENaC, binds WNK4 and specifically phosphorylates it at serine 1169. Mutations that mimic this phosphorylation abrogate WNK4’s inhibition of ENaC. We also measured amiloride‐sensitive short circuit currents in distal colonic epithelial explants and showed that PHAII mice exhibit 3.5‐fold increased ENaC activity (p<0.02) compared to wild type littermates. These studies identify a novel downstream target of WNK4 and show that WNK4 itself is regulated by components of the aldosterone signaling pathway. Moreover, they provide the first functional demonstration of a WNK kinase regulating an ion channel in vivo and reveal a novel role for WNK kinases in regulating salt absorption outside the kidney.