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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 abundance and phosphorylation levels also decrease below the wild-type level in the double-mutant mice but remain higher than in SPAK 243A/243A mice. This is different from what was observed in WNK4-FHHt mice in which SPAK 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 SPAK, they suggest that WNK1 and WNK4 play different roles in the distal nephron. Familial Hyperkaliaemic Hypertension (FHHt), also known as Gordon's syndrome or Pseudohypoaldosteronism type II (PHAII), is a rare genetic form of hypertension associated with hyperkalemia and metabolic hyperchlo-remic acidosis (OMIM #145260) 1. All these symptoms are corrected by thiazide diuretics, which inhibit the activity of the Na +-Cl − transporter NCC, encoded by the SLC12A3 gene 1. FHHt is caused by mutations in one of at least four genes: WNK1 [With No lysine (K) 1], WNK4, KLHL3 (Kelch-Like family member 3), and CUL3 (cullin-3) 2-4. The associated proteins belong to the same regulatory pathway, as WNK1 and WNK4 are recruited by KLHL3 for ubiquitination by the Cul3-E3 RING-type ubiquitin-ligase complex 5. The sensitivity of patients to thiazide diuretics strongly suggested that FHHt is mainly caused by a gain of activity of NCC in the distal nephron. The role of NCC in regulating blood pressure has been established by the discovery of inactivating mutations of the SLC12A3 gene, which cause Gitelman's syndrome, an inherited disorder that is the mirror image of FHHt, with arterial hypotension, renal salt wasting and hypokalemic metabolic alkalosis (OMIM #263800) 6,7. Therefore, several studies focused on the mechanisms underlying the regulation of NCC by WNK1 and WNK4. In vitro studies have demonstrated that the WNKs activate two kinases, SPAK (Ste20-related Proline/ Alanine-rich Kinase) and OSR1 (oxidative stress-responsive kinase 1) 8 , which can in turn phosphorylate and activate NCC 9. SPAK and OSR1 can also activate the Na +-K +-2Cl − cotransporters, NKCC1 and NKCC2, and inhibit the K +-Cl − cotransporters, KCC1-4 10. In vivo, the expression and phosphorylation of NCC is reduced
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Submitted on : Wednesday, October 17, 2018 - 10:25:10 AM
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SPAK inactivation in. WNK1-FHH...
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Chloé Rafael, Christelle Soukaseum, Véronique Baudrie, Perrine Frère, Juliette Hadchouel. Consequences of SPAK inactivation on Hyperkalemic Hypertension caused by WNK1 mutations: evidence for differential roles of WNK1 and WNK4. Scientific Reports, Nature Publishing Group, 2018, 8 (1), pp.3249. ⟨10.1038/s41598-018-21405-x⟩. ⟨inserm-01897387⟩



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