WNK1 promotes water homeostasis by acting as a central osmolality sensor for arginine vasopressin release

Xin Jin; Jian Xie; Chia-Wei Yeh; Jen-Chi Chen; Chih-Jen Cheng; Cheng-Chang Lien; Chou-Long Huang

doi:10.1172/JCI164222

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WNK1 promotes water homeostasis by acting as a central osmolality sensor for arginine vasopressin release

Journal article

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Peer reviewed

WNK1 promotes water homeostasis by acting as a central osmolality sensor for arginine vasopressin release

Xin Jin, Jian Xie, Chia-Wei Yeh, Jen-Chi Chen, Chih-Jen Cheng, Cheng-Chang Lien and Chou-Long Huang

The Journal of clinical investigation, Vol.133(11), e164222

06/01/2023

DOI: 10.1172/JCI164222

PMCID: PMC10231991

PMID: 37071482

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Abstract

Maintaining internal osmolality constancy is essential for life. Release of arginine vasopressin (AVP) responding to hyperosmolality is critical. Current hypotheses for osmolality sensors in circumventricular organs of the brain (CVOs) focus on mechanosensitive membrane proteins. The present study demonstrated that an intracellular protein kinase WNK1 was involved. Focusing on vascular-organ-of-lamina-terminalis (OVLT) nuclei, we showed that WNK1 kinase was activated by water restriction. Neuronal-specific knockout (cKO) of Wnk1 caused polyuria with decreased urine osmolality that persisted in water restriction and blunted water restriction-induced AVP release. Wnk1-cKO also blunted mannitol-indued AVP release but had no effect on osmotic thirst response. The role of WNK1 in the osmosensory neurons in CVOs was supported by neuronal pathway tracing. Hyperosmolality-induced increases in action potential firing in OVLT neurons was blunted by Wnk1 deletion or pharmacological WNK inhibitors. Knockdown of Kv3.1 channel in OVLT by shRNA reproduced the phenotypes. Thus, WNK1 in osmosensory neurons in CVOs detects extracellular hypertonicity and mediates the increase in AVP release by activating Kv3.1 and increasing action potential firing from osmosensory neurons.

Endocrinology

Ion Channels

Nephrology

Transport

Epithelial transport of ions and water

Details

Title: Subtitle: WNK1 promotes water homeostasis by acting as a central osmolality sensor for arginine vasopressin release
Creators: Xin Jin - University of Iowa
Jian Xie - University of Iowa
Chia-Wei Yeh - National Yang Ming Chiao Tung University
Jen-Chi Chen - University of Iowa
Chih-Jen Cheng - University of Iowa
Cheng-Chang Lien - National Yang Ming Chiao Tung University
Chou-Long Huang - University of Iowa
Resource Type: Journal article
Publication Details: The Journal of clinical investigation, Vol.133(11), e164222
DOI: 10.1172/JCI164222
PMID: 37071482
PMCID: PMC10231991
NLM abbreviation: J Clin Invest
eISSN: 1558-8238
Grant note: DOI: 10.13039/100000062, name: NIDDK, award: DK111542 to C.-L. H, DK134420 to C.-J. C
Language: English
Electronic publication date: 04/18/2023
Date published: 06/01/2023
Academic Unit: Nephrology; Internal Medicine
Record Identifier: 9984398348602771

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