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WNK-SPAK-NKCC1/KCC2 pathway disrupts chloride homeostasis and drives hyperactivation of PVN-CRH neurons in essential hypertension.

Overview

Authors: Xinqi Guo1, Hongyu Ma1, Qiyue Zhao1, Ying Zhang1, Peiyun Yang1, Qian Zhao1, Lu Jia1, Liping Zhang1, Yue Guan1,2, Yuanyuan Zhang3, Suibing Miao4, Huijie Ma1,2,5
  1. Department of Physiology, Hebei Medical University, Shijiazhuang 050017, China
  2. Key Laboratory of Neurophysiology of Hebei Province, Shijiazhuang, Hebei 050017, China
  3. School of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang, Hebei 050200, China
  4. Institute of Reproductive Medicine of Shijiazhuang, The Fourth Hospital of Shijiazhuang, Gynecology and Obstetrics Hospital Affiliated to Hebei Medical University, Shijiazhuang 050011, China
  5. The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang 050017, China
Institutions: Hebei Medical University (China); Fourth Hospital of Hebei Medical University (China)
Journal: iScience, volume 29, issue 7, article 116593
Dates: received 31 October 2025; accepted 11 June 2026; published online 24 June 2026
Type: Research article · Language: English
License: CC BY-NC
Identifiers: DOI 10.1016/j.isci.2026.116593 · PMID 42491700 · PMCID PMC13378147 · OpenAlex W7165751073
Open access: gold, a free copy (OpenAlex)
Status: code on request
Categories: other condition (population), cellular / molecular (subfield)
Methods: Spectral & time-frequency, Statistics, Single-unit activity, calcium imaging
Keywords: corticotropin-releasing hormone neuron, hypothalamic paraventricular nucleus, chloride homeostasis, WNK-SPAK-NKCC1/KCC2 pathway, hypertension
Topic: Sodium Intake and Health (Nutrition and Dietetics, Nursing), according to OpenAlex
Funding: National Natural Science Foundation of China (National Science Foundation of China) (31971044, 82571813); Natural Science Foundation of Hebei Province (H2019206325, C2021106015); Key laboratory of Neural and Vascular Biology, Ministry of Education of China (NV20210004); Natural Science Foundation of Hebei Province for Innovative Research Group Project (H2025206897); Hebei Postgraduate Innovation Grant Program (CXZZBS2022081, XCXZZB202317)
Citations: not cited yet (Europe PMC); 63 references in the paper
Research resources: Antibodies Rabbit anti-KCC2 antibody RRID:AB_10638485, RRID:AB_11205577, Antibodies Rabbit anti-NKCC1 antibody RRID:AB_2188522, Antibodies Rabbit anti-WNK2 antibody RRID:AB_2553911, Goat anti-rabbit IgG-HRP RRID:AB_2722564, Goat anti-mouse IgG-HRP RRID:AB_2722565, Antibodies Rabbit anti-CRH antibody RRID:AB_2758463, Antibodies Rabbit anti-β-actin antibody RRID:AB_2768234, Antibodies Rabbit anti-SPAK antibody RRID:AB_2862985, Antibodies Rabbit anti-WNK1 antibody RRID:AB_2923673, Antibodies Rabbit anti-WNK4 antibody RRID:AB_922775

Abstract

Hyperactivity of hypothalamic corticotropin-releasing hormone (CRH) neurons contributes to elevated sympathetic outflow in hypertension, but the underlying mechanisms remain unclear. Here, we demonstrate that activation of the WNK-SPAK-NKCC1/KCC2 pathway disrupts chloride homeostasis in paraventricular nucleus (PVN) CRH neurons, diminishing GABAergic inhibition and driving neuronal hyperactivity in spontaneously hypertensive rats (SHRs). Chemogenetic inhibition of PVN-CRH neurons reduced blood pressure and renal sympathetic nerve activity in SHRs. We found depolarizing shifts in GABA reversal potential (EGABA) and elevated intracellular chloride concentrations ([Cl−]i) in PVN-CRH neurons of SHRs, associated with increased phosphorylation of NKCC1 (Thr212/Thr217) and KCC2 (Thr1007). Upstream WNK1/4 and phospho-SPAK (Ser373) were upregulated in the PVN of SHRs. Pharmacological inhibition of WNK or SPAK shifted EGABA toward more hyperpolarized values, reduced PVN-CRH neuronal excitability, and lowered blood pressure in SHRs. These findings identify the WNK-SPAK-NKCC1/KCC2 pathway as a promising therapeutic target for neurogenic hypertension.

Reproduced under the paper's license (CC BY-NC), from the paper cited above.

Code

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Data

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Data and code availability

• All data reported in this paper will be shared by the lead contact upon request. • This paper does not report original code. • Any additional information required to reanalyze the data reported in this work paper is available from the lead contact upon request.

Reproduced under the paper's license (CC BY-NC), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 12 authors, 5 keywords, 5 funders, 63 references, 11 RRIDs.

Cite

This paper

Guo, X., Ma, H., Zhao, Q., Zhang, Y., Yang, P., Zhao, Q., Jia, L., Zhang, L., Guan, Y., Zhang, Y., Miao, S., & Ma, H. (2026). WNK-SPAK-NKCC1/KCC2 pathway disrupts chloride homeostasis and drives hyperactivation of PVN-CRH neurons in essential hypertension. iScience, 29(7), 116593. https://doi.org/10.1016/j.isci.2026.116593

BibTeX

@article{guo2026wnk,
author = {Guo, Xinqi and Ma, Hongyu and Zhao, Qiyue and Zhang, Ying and Yang, Peiyun and Zhao, Qian and Jia, Lu and Zhang, Liping and Guan, Yue and Zhang, Yuanyuan and Miao, Suibing and Ma, Huijie},
title = {{WNK-SPAK-NKCC1/KCC2 pathway disrupts chloride homeostasis and drives hyperactivation of PVN-CRH neurons in essential hypertension}},
journal = {iScience},
year = {2026},
month = jun,
volume = {29},
number = {7},
pages = {116593},
publisher = {Elsevier},
issn = {2589-0042},
doi = {10.1016/j.isci.2026.116593},
url = {https://doi.org/10.1016/j.isci.2026.116593},
pmid = {42491700},
pmcid = {PMC13378147}
}

RIS

TY - JOUR
AU - Guo, Xinqi
AU - Ma, Hongyu
AU - Zhao, Qiyue
AU - Zhang, Ying
AU - Yang, Peiyun
AU - Zhao, Qian
AU - Jia, Lu
AU - Zhang, Liping
AU - Guan, Yue
AU - Zhang, Yuanyuan
AU - Miao, Suibing
AU - Ma, Huijie
TI - WNK-SPAK-NKCC1/KCC2 pathway disrupts chloride homeostasis and drives hyperactivation of PVN-CRH neurons in essential hypertension
T2 - iScience
J2 - iScience
PY - 2026
DA - 2026/06/24
VL - 29
IS - 7
SP - 116593
SN - 2589-0042
PB - Elsevier
DO - 10.1016/j.isci.2026.116593
UR - https://doi.org/10.1016/j.isci.2026.116593
LA - en
ER -

CSL-JSON

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