NF-κB Signaling-Mediated Activation of WNK-SPAK-NKCC1 Cascade in Worsened Stroke Outcomes of Ang II-Hypertensive Mice.

Autor:	Bhuiyan MIH; Departments of Neurology (M.I.H.B., C.B.Y., I.J., M.N.H., S.F., H.H., B.J.M., D.S.), University of Pittsburgh, PA.; Pittsburgh Institute for Neurodegenerative Disorders (M.I.H.B., C.B.Y., I.J., M.N.H., S.F., B.J.M., D.S.), University of Pittsburgh, PA.; Veterans Affairs Pittsburgh Health Care System, Geriatric Research, Educational, and Clinical Center, PA (M.I.H.B.' D.S.)., Young CB; Departments of Neurology (M.I.H.B., C.B.Y., I.J., M.N.H., S.F., H.H., B.J.M., D.S.), University of Pittsburgh, PA.; Pittsburgh Institute for Neurodegenerative Disorders (M.I.H.B., C.B.Y., I.J., M.N.H., S.F., B.J.M., D.S.), University of Pittsburgh, PA., Jahan I; Departments of Neurology (M.I.H.B., C.B.Y., I.J., M.N.H., S.F., H.H., B.J.M., D.S.), University of Pittsburgh, PA.; Pittsburgh Institute for Neurodegenerative Disorders (M.I.H.B., C.B.Y., I.J., M.N.H., S.F., B.J.M., D.S.), University of Pittsburgh, PA., Hasan MN; Departments of Neurology (M.I.H.B., C.B.Y., I.J., M.N.H., S.F., H.H., B.J.M., D.S.), University of Pittsburgh, PA.; Pittsburgh Institute for Neurodegenerative Disorders (M.I.H.B., C.B.Y., I.J., M.N.H., S.F., B.J.M., D.S.), University of Pittsburgh, PA., Fischer S; Departments of Neurology (M.I.H.B., C.B.Y., I.J., M.N.H., S.F., H.H., B.J.M., D.S.), University of Pittsburgh, PA.; Pittsburgh Institute for Neurodegenerative Disorders (M.I.H.B., C.B.Y., I.J., M.N.H., S.F., B.J.M., D.S.), University of Pittsburgh, PA., Meor Azlan NF; Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Exeter, United Kingdom (N.F.M.A., J.Z.)., Liu M; Medicine (M.L., D.G.), University of Pittsburgh, PA., Chattopadhyay A; Molecular Biology-Information Service, Health Sciences Library System (A.C.), University of Pittsburgh, PA., Huang H; Departments of Neurology (M.I.H.B., C.B.Y., I.J., M.N.H., S.F., H.H., B.J.M., D.S.), University of Pittsburgh, PA., Kahle KT; Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston (K.T.K.)., Zhang J; Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Exeter, United Kingdom (N.F.M.A., J.Z.)., Poloyac SM; College of Pharmacy, University of Texas, Austin (S.M.P)., Molyneaux BJ; Departments of Neurology (M.I.H.B., C.B.Y., I.J., M.N.H., S.F., H.H., B.J.M., D.S.), University of Pittsburgh, PA.; Pittsburgh Institute for Neurodegenerative Disorders (M.I.H.B., C.B.Y., I.J., M.N.H., S.F., B.J.M., D.S.), University of Pittsburgh, PA., Straub AC; Pharmacology and Chemical Biology (A.C.S), University of Pittsburgh, PA.; Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute (A.C.S., D.G.), University of Pittsburgh, PA., Deng X; State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian, China (X.D.)., Gomez D; Medicine (M.L., D.G.), University of Pittsburgh, PA.; Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute (A.C.S., D.G.), University of Pittsburgh, PA., Sun D; Departments of Neurology (M.I.H.B., C.B.Y., I.J., M.N.H., S.F., H.H., B.J.M., D.S.), University of Pittsburgh, PA.; Pittsburgh Institute for Neurodegenerative Disorders (M.I.H.B., C.B.Y., I.J., M.N.H., S.F., B.J.M., D.S.), University of Pittsburgh, PA.; Veterans Affairs Pittsburgh Health Care System, Geriatric Research, Educational, and Clinical Center, PA (M.I.H.B.' D.S.).
Jazyk:	angličtina
Zdroj:	Stroke [Stroke] 2022 May; Vol. 53 (5), pp. 1720-1734. Date of Electronic Publication: 2022 Mar 11.
DOI:	10.1161/STROKEAHA.121.038351
Abstrakt:	Background: Worsened stroke outcomes with hypertension comorbidity are insensitive to blood pressure-lowering therapies. In an experimental stroke model with comorbid hypertension, we investigated causal roles of ang II (angiotensin II)-mediated stimulation of the brain WNK (with no lysine [K] kinases)-SPAK (STE20/SPS1-related proline/alanine-rich kinase)-NKCC1 (Na-K-Cl cotransporter) complex in worsened outcomes. Methods: Saline- or ang II-infused C57BL/6J male mice underwent stroke induced by permanent occlusion of the distal branches of the middle cerebral artery. Mice were randomly assigned to receive either vehicle dimethyl sulfoxide/PBS (2 mL/kg body weight/day, IP), a novel SPAK inhibitor, 5-chloro-N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)-2-hydroxybenzamide (ZT-1a' 5 mg/kg per day, IP) or a NF-κB (nuclear factor-κB) inhibitor TAT-NBD (transactivator of transcription-NEMO-binding domain' 20 mg/kg per day, IP). Activation of brain NF-κB and WNK-SPAK-NKCC1 cascade as well as ischemic stroke outcomes were examined. Results: Stroke triggered a 2- to 5-fold increase of WNK (isoforms 1, 2, 4), SPAK/OSR1 (oxidative stress-responsive kinase 1), and NKCC1 protein in the ang II-infused hypertensive mouse brains at 24 hours after stroke, which was associated with increased nuclear translocation of phospho-NF-κB protein in the cortical neurons (a Pearson correlation r of 0.77, P <0.005). The upregulation of WNK-SPAK-NKCC1 cascade proteins resulted from increased NF-κB recruitment on Wnk1, Wnk2, Wnk4, Spak , and Nkcc1 gene promoters and was attenuated by NF-κB inhibitor TAT-NBD. Poststroke administration of SPAK inhibitor ZT-1a significantly reduced WNK-SPAK-NKCC1 complex activation, brain lesion size, and neurological function deficits in the ang II-hypertensive mice without affecting blood pressure and cerebral blood flow. Conclusions: The ang II-induced stimulation of NF-κB transcriptional activity upregulates brain WNK-SPAK-NKCC1 cascade and contributes to worsened ischemic stroke outcomes, illustrating the brain WNK-SPAK-NKCC1 complex as a therapeutic target for stroke with comorbid hypertension.
Databáze:	MEDLINE
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