@article{c6e7cb808c5d4e61aa8bb32f632e06c1,
title = "WNK1 promotes water homeostasis by acting as a central osmolality sensor for arginine vasopressin release",
abstract = "Maintaining internal osmolality constancy is essential for life. Release of arginine vasopressin (AVP) in response to hyperosmolality is critical. Current hypotheses for osmolality sensors in circumventricular organs (CVOs) of the brain focus on mechanosensitive membrane proteins. The present study demonstrated that 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. Neuron-specific conditional KO (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-induced 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.",
author = "Xin Jin and Jian Xie and Yeh, {Chia Wei} and Chen, {Jen Chi} and Cheng, {Chih Jen} and Lien, {Cheng Chang} and Huang, {Chou Long}",
note = "Funding Information: We thank Baojian Xue and Alan Kim Johnson at the University of Iowa College of Arts and Sciences for assistance with isolation of brain regions; Maniselvan Kuppusamy for participation in the preliminary stage of experiments; Paul McCray for tdTomato-EGFP reporter mice; the Transgenic Mouse Model Core Facility of the National Core Facility for Biopharmaceuticals; and Ministry of Science and Technology, Taiwan, and the Gene Knockout Mouse Core Laboratory of National Taiwan University Center of Genomic and Precision Medicine for assistance in generating Cl–-insensitive Wnk1-cKI mice. This work was supported in part by the NIH (DK111542 to CLH; DK134420 to CJC); the Brain Research Center, National Yang Ming Chiao Tung University (to CCL); and Ministry of Science and Technology, Taiwan (MOST 109-2314-B-016-039-MY3 to CJC; 111-2320-B-A49-009-MY3 and 111-2321-B-A49-005 to CCL). CLH holds the Roy J. Carver Chair in Internal Medicine at the University of Iowa Carver College of Medicine. Funding Information: We thank Baojian Xue and Alan Kim Johnson at the University of Iowa College of Arts and Sciences for assistance with isolation of brain regions; Maniselvan Kuppusamy for participation in the preliminary stage of experiments; Paul McCray for tdTomato-EGFP reporter mice; the Transgenic Mouse Model Core Facility of the National Core Facility for Biopharmaceuticals; and Ministry of Science and Technology, Taiwan, and the Gene Knockout Mouse Core Laboratory of National Taiwan University Center of Genomic and Precision Medicine for assistance in generating Cl-insensitive Wnk1-cKI mice. This work was supported in part by the NIH (DK111542 to CLH; DK134420 to CJC); the Brain Research Center, National Yang Ming Chiao Tung University (to CCL); and Ministry of Science and Technology, Taiwan (MOST 109-2314-B-016-039-MY3 to CJC; 111-2320-B-A49-009-MY3 and 111-2321-B-A49-005 to CCL). CLH holds the Roy J. Carver Chair in Internal Medicine at the University of Iowa Carver College of Medicine. Publisher Copyright: Copyright: {\textcopyright} 2023, Jin et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.",
year = "2023",
month = jun,
day = "1",
doi = "10.1172/JCI164222",
language = "English (US)",
volume = "133",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "11",
}