SPAK Deficiency Corrects Pseudohypoaldosteronism II Caused by WNK4 Mutation

Pei-Yi Chu; Chih-Jen Cheng; Yi-Chang Wu; Yu-Wei Fang; Tom Chau; Shinichi Uchida; Sei Sasaki; Sung-Sen Yang; Shih-Hua Lin

doi:10.1371/journal.pone.0072969

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SPAK Deficiency Corrects Pseudohypoaldosteronism II Caused by WNK4 Mutation

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SPAK Deficiency Corrects Pseudohypoaldosteronism II Caused by WNK4 Mutation

Pei-Yi Chu, Chih-Jen Cheng, Yi-Chang Wu, Yu-Wei Fang, Tom Chau, Shinichi Uchida, Sei Sasaki, Sung-Sen Yang and Shih-Hua Lin

PloS one, Vol.8(9), pp.e72969-e72969

09/11/2013

DOI: 10.1371/journal.pone.0072969

PMCID: PMC3770638

PMID: 24039833

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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.

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Title: Subtitle: SPAK Deficiency Corrects Pseudohypoaldosteronism II Caused by WNK4 Mutation
Creators: Pei-Yi Chu - National Defense Medical Center
Chih-Jen Cheng - Tri-Service General Hospital
Yi-Chang Wu - Taoyuan Armed Forces General Hospital
Yu-Wei Fang - National Defense Medical Center
Tom Chau - Providence St. Vincent Medical Center
Shinichi Uchida - Tokyo Medical and Dental University
Sei Sasaki - Tokyo Medical and Dental University
Sung-Sen Yang - National Defense Medical Center
Shih-Hua Lin - National Defense Medical Center
Resource Type: Journal article
Publication Details: PloS one, Vol.8(9), pp.e72969-e72969
DOI: 10.1371/journal.pone.0072969
PMID: 24039833
PMCID: PMC3770638
NLM abbreviation: PLoS One
ISSN: 1932-6203
eISSN: 1932-6203
Publisher: Public Library Science
Number of pages: 12
Grant note: TSGH-C-101-113 / Research Fund of Tri-Service General Hospital NSC-100-2314-B-016-018-MY3; NSC-100-2314-B-016-019-MY3 / NSC, Taiwan; Ministry of Science and Technology, Taiwan Japan-Taiwan Joint Research Program, Interchange Association, Japan
Language: English
Date published: 09/11/2013
Academic Unit: Nephrology; Internal Medicine
Record Identifier: 9984383927302771

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