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

ABSTRACT: 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 SPAK (Ste20-related Proline/Alanine-rich Kinase) plays a dominant role in the development of FHHt caused by WNK4 mutations. The implication of SPAK in FHHt caused by WNK1 mutation has never been investigated. To clarify this issue, we crossed WNK1^+/FHHt mice with SPAK knock-in mice in which the T-loop Thr243 residue was mutated to alanine to prevent activation by WNK kinases. We show that WNK1^+/FHHT:SPAK ^243A/243A mice display an intermediate phenotype, between that of control and SPAK ^243A/243A mice, with normal blood pressure but hypochloremic metabolic alkalosis. NCC abund

SUBMITTER: Rafael C 

PROVIDER: S-EPMC5818654 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature