SPAK deficiency corrects pseudohypoaldosteronism II caused by WNK4 mutation

PLoS One. 2013 Sep 11;8(9):e72969. doi: 10.1371/journal.pone.0072969. eCollection 2013.

Abstract

Stimulation of the OSR1 (Oxidative stress-responsive kinase-1)/SPAK [STE20 (sterile 20)/SPS1-related proline/alanine-rich kinase]-NCC (Na(+)-Cl(-) cotransporter) signaling cascade plays an important role in the WNK [With-No-Lysine (K)] kinase 4 D561A knock-in mouse model of pseudohypoaldosteronism type II (PHA II) characterized by salt-sensitive hypertension and hyperkalemia. The aim of this study was to investigate the respective roles of Osr1 and Spak in the pathogenesis of PHA II in vivo. Wnk4 (D561A/+) mice were crossed with kidney tubule-specific (KSP) Osr1 knockout (KSP-Osr1 (-/-)) and Spak knockout (Spak (-/-)) mice. Blood pressure, plasma and urine biochemistries, and the relevant protein expression in the kidneys were examined. Wnk4 (D561A/+), KSP-Osr1 (-/-), and Spak (-/-) mice recapitulated the phenotypes of PHA II, Bartter-like syndrome, and Gitelman syndrome, respectively. Wnk4 (D561A/+).KSP-Osr1 (-/-) remained phenotypically PHA II while Wnk4 (D561A/+).Spak (-/-) mice became normotensive and lacked the PHA II phenotype. Phosphorylated Spak and Ncc were similarly increased in both Wnk4 (D561A/+) and Wnk4 (D561A/+).KSP-Osr1 (-/-) mice while phosphorylated Ncc normalized in Wnk4 (D561A/+).Spak (-/-) mice. Furthermore, Wnk4 (D561A/+).KSP-Osr1 (-/-) mice exhibited exaggerated salt excretion in response to thiazide diuretics while Wnk4 (D561A/+).Spak (-/-) mice exhibited normal responses. Wnk4(D561A/+).Spak (-/-).KSP-Osr1 (-/-) triple mutant mice had low blood pressure and diminished phosphorylated Ncc. Both SPAK and OSR1 are important in the maintenance of blood pressure but activation of SPAK-NCC plays the dominant role in PHA II. SPAK may be a therapeutic target for disorders with salt-sensitive hypertension related to WNK4 activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chlorides / urine
  • Disease Models, Animal
  • Diuretics / pharmacology
  • Gene Deletion
  • Genetic Association Studies
  • Genotype
  • Mice
  • Mice, Knockout
  • Mutation*
  • Phenotype
  • Phosphorylation
  • Protein Serine-Threonine Kinases / deficiency*
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / metabolism
  • Pseudohypoaldosteronism / genetics*
  • Pseudohypoaldosteronism / metabolism
  • Sodium / urine
  • Solute Carrier Family 12, Member 1 / metabolism
  • Solute Carrier Family 12, Member 3 / metabolism

Substances

  • Chlorides
  • Diuretics
  • Slc12a3 protein, mouse
  • Solute Carrier Family 12, Member 1
  • Solute Carrier Family 12, Member 3
  • Sodium
  • Prkwnk4 protein, mouse
  • Stk39 protein, mouse
  • OXSR1 protein, mouse
  • Protein Serine-Threonine Kinases

Grants and funding

This study was supported in part by a grant from the NSC, Taiwan (NSC-100-2314-B-016-018-MY3; NSC-100-2314-B-016-019-MY3) and by a grant from the Research Fund of Tri-Service General Hospital (TSGH-C-101-113), and Japan-Taiwan Joint Research Program, Interchange Association, Japan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.