NCC regulation by WNK signal cascade.

With-no-lysine (K) (WNK) kinases have been identified as the causal genes for pseudohypoaldosteronism type II (PHAII), a rare hereditary hypertension condition characterized by hyperkalemia, hyperchloremic metabolic acidosis, and thiazide-hypersensitivity. We thought that clarifying the link between WNK and NaCl cotransporter (NCC) would bring us new mechanism(s) of NCC regulation. For the first time, we were able to produce a knock-in mouse model of PHAII and anti-phosphorylated NCC antibodies against the putative NCC phosphorylation sites and discover that constitutive activation of NCC and increased phosphorylation of NCC are the primary pathogenesis of the disease . We have since demonstrated that this regulatory mechanism is mediated by the kinases oxidative stress-response protein 1 (OSR1) and STE20/SPS1-related proline/alanine-rich kinase (SPAK) (WNK-OSR1/SPAK-NCC signaling cascade) and that the signaling is not only important in the pathological condition of PHAII but also plays a crucial physiological role in the regulation of NCC.