Central Osmolality Sensing for Arginine Vasopressin Release Is Mediated by WNK1-OSR1/SPAK-Kv3.1 Cascade

Xin Jin; Jian Xie; Chia-Wei Yeh; Yu-Jui Li; Cheng-Chang Lien; Chou-Long Huang

doi:10.1096/fj.202502072RR

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Central Osmolality Sensing for Arginine Vasopressin Release Is Mediated by WNK1-OSR1/SPAK-Kv3.1 Cascade

Journal article

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Central Osmolality Sensing for Arginine Vasopressin Release Is Mediated by WNK1-OSR1/SPAK-Kv3.1 Cascade

Xin Jin, Jian Xie, Chia-Wei Yeh, Yu-Jui Li, Cheng-Chang Lien and Chou-Long Huang

The FASEB journal, Vol.39(22), e71213

11/30/2025

DOI: 10.1096/fj.202502072RR

PMCID: PMC12621171

PMID: 41246868

Appears in UI Libraries Support Open Access

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Abstract

Life depends on maintaining water homeostasis and internal osmolality constancy. In terrestrial animals, the release of the antidiuretic hormone arginine vasopressin (AVP) in response to variations of extracellular osmolality (tonicity) is crucial. We have reported that WNK1 kinase in the vascular-organ-of-lamina-terminalis (OVLT) nuclei of the brain mediates the hypertonicity-induced AVP release by activating the voltage-gated K channel Kv3.1 increasing action potential firing. The downstream mechanism for WNK1-mediated osmosensation is unknown. Here, we showed that the hypertonicity-induced increases in Kv3.1 currents in cultured cells required the oxidative stress-responsive-1 (OSR1) or STE20/SPS1-related proline/alanine-rich (SPAK) kinase. Both kinases were present in the mouse OVLT area. Hypertonicity induced by water restriction or mannitol injection increased the abundance of phosphorylated OSR1 and SPAK in the OVLT. Double deletion of Osr1 and Spak in the OVLT in mice caused polyuria with relative hypotonic urine that persisted in water restriction. The water restriction-induced AVP release was blunted in Osr1 and Spak-deleted mice. In brain slice recordings, the hypertonicity-induced increases in action potential firing in OVLT were blunted by Osr1 and Spak deletion. Deletion of the Kv3.1 channel in the OVLT showed a similar phenotype. Expression of the constitutively active OSR1 in the OVLT resulted in increased AVP release and inappropriate antidiuretic hormone secretion phenotype. In summary, OSR1/SPAK acts downstream of WNK1 to regulate AVP release in response to hypertonicity. In OVLT neurons OSR1/SPAK activates Kv3.1 to increase action potential firing. Thus, the WNK1-OSR1/SPAK-Kv3.1 cascade regulates water homeostasis and AVP release to control osmolality stability.

Signal Transduction

Animals

Arginine Vasopressin - metabolism

Male

Mice

Mice, Inbred C57BL

Mice, Knockout

Osmolar Concentration

Protein Serine-Threonine Kinases - genetics

Protein Serine-Threonine Kinases - metabolism

WNK Lysine-Deficient Protein Kinase 1 - genetics

WNK Lysine-Deficient Protein Kinase 1 - metabolism

UIOWA OA Agreement

Details

Title: Subtitle: Central Osmolality Sensing for Arginine Vasopressin Release Is Mediated by WNK1-OSR1/SPAK-Kv3.1 Cascade
Creators: Xin Jin - University of Iowa
Jian Xie - University of Iowa
Chia-Wei Yeh - National Yang Ming Chiao Tung University
Yu-Jui Li - National Yang Ming Chiao Tung University
Cheng-Chang Lien - National Yang Ming Chiao Tung University
Chou-Long Huang - University of Iowa
Resource Type: Journal article
Publication Details: The FASEB journal, Vol.39(22), e71213
DOI: 10.1096/fj.202502072RR
PMID: 41246868
PMCID: PMC12621171
NLM abbreviation: FASEB J
ISSN: 0892-6638
eISSN: 1530-6860
Publisher: Wiley
Grant note: HHS | NIH | NIDDK | Division of Diabetes, Endocrinology, and Metabolic Diseases (DEM) the Ministry of Science and Technology
Language: English
Date published: 11/30/2025
Academic Unit: Nephrology; Internal Medicine
Record Identifier: 9985033763602771

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