Consequences of SPAK inactivation on Hyperkalemic Hypertension caused by WNK1 mutations: evidence for differential roles of WNK1 and WNK4.

Mutations of the gene encoding WNK1 [With No lysine (K) kinase 1] or WNK4 cause Familial Hyperkalemic Hypertension (FHHt). Previous studies have shown that the activation of (Ste20-related Proline/Alanine-rich Kinase) plays a dominant role in the development of FHHt caused by WNK4 mutations. The implication of duanyu1842K in FHHt caused by WNK1 mutation has never been investigated. To clarify this issue, we crossed WNK1^+/FHHt mice with duanyu1842K knock-in mice in which the T-loop Thr243 residue was mutated to alanine to prevent activation by WNK kinases. We show that ^243A/243A mice display an intermediate phenotype, between that of control and duanyu1842K ^243A/243A mice, with normal blood pressure but hypochloremic metabolic alkalosis. NCC abundance and phosphorylation levels also decrease below the wild-type level in the double-mutant mice but remain higher than in duanyu1842K ^243A/243A mice. This is different from what was observed in WNK4-FHHt mice in which duanyu1842K inactivation completely restored the phenotype and NCC expression to wild-type levels. Although these results confirm that FHHt caused by WNK1 mutations is dependent on the activation of they suggest that WNK1 and WNK4 play different roles in the distal nephron.

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