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

Chloé Rafael,Véronique Baudrie,Juliette Hadchouel,Christelle Soukaseum,Perrine Frère

doi:10.1038/s41598-018-21405-x

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:SPAK243A/243A mice display an intermediate phenotype, between that of control and SPAK243A/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 SPAK243A/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.

Highlights

Familial Hyperkaliaemic Hypertension (FHHt), known as Gordon’s syndrome or Pseudohypoaldosteronism type II (PHAII), is a rare genetic form of hypertension associated with hyperkalemia and metabolic hyperchloremic acidosis (OMIM #145260)[1]
Several studies have demonstrated that the activation of SPAK, but not OSR1, by WNK4 is a key step in the pathogenesis of FHHt
We used a mouse model to investigate the consequences of SPAK inactivation in the pathogenesis of FHHt caused by WNK1 mutation

Summary

Introduction

Familial Hyperkaliaemic Hypertension (FHHt), known as Gordon’s syndrome or Pseudohypoaldosteronism type II (PHAII), is a rare genetic form of hypertension associated with hyperkalemia and metabolic hyperchloremic 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]. Several studies have demonstrated that the activation of SPAK, but not OSR1, by WNK4 is a key step in the pathogenesis of FHHt. First, SPAK abundance and phosphorylation are increased in a mouse model of FHHt caused by a missense mutation of WNK4 (Wnk4D561/+ mice)[14]. Wnk4D561/+ mice bearing a OSR1 inactivation in the nephron (Wnk 4D561/+:KSP-Osr1−/−) still display a complete FHHt phenotype[16], even though OSR1 deficiency in the nephron causes hypokalemia under normal diet and systolic hypotension when mice are fed a low Na+ diet[17]

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