title: Deletion of the WNK3-SPAK kinase complex in mice improves radiographic and clinical outcomes in malignant cerebral edema after ischemic stroke.
abstract: The WNK-SPAK kinase signaling pathway controls renal NaCl reabsorption and systemic blood pressure by regulating ion transporters and channels. A WNK3-SPAK complex is highly expressed in brain, but its function in this organ remains unclear. Here, we investigated the role of this kinase complex in brain edema and white matter injury after ischemic stroke. Wild-type, WNK3 knockout, and SPAK heterozygous or knockout mice underwent transient middle cerebral artery occlusion. One cohort of mice underwent magnetic resonance imaging. Ex-vivo brains three days post-ischemia were imaged by slice-selective spin-echo diffusion tensor imaging magnetic resonance imaging, after which the same brain tissues were subjected to immunofluorescence staining. A second cohort of mice underwent neurological deficit analysis up to 14 days post-transient middle cerebral artery occlusion. Relative to wild-type mice, WNK3 knockout, SPAK heterozygous, and SPAK knockout mice each exhibited a >50% reduction in infarct size and associated cerebral edema, significantly less demyelination, and improved neurological outcomes. We conclude that WNK3-SPAK signaling regulates brain swelling, gray matter injury, and demyelination after ischemic stroke, and that WNK3-SPAK inhibition has therapeutic potential for treating malignant cerebral edema in the setting of middle cerebral artery stroke.
authors: 1 Department of Neurology, the First Affiliated Hospital of the Harbin Medical University, Harbin, China.|2 Department of Neurology, University of Pittsburgh, Pittsburgh, USA.
authors: Hanshu
authors: H
authors: Zhao
authors: 2 Department of Neurology, University of Pittsburgh, Pittsburgh, USA.
authors: Rachel
authors: R
authors: Nepomuceno
authors: 2 Department of Neurology, University of Pittsburgh, Pittsburgh, USA.|3 Department of Neurological Surgery, the Second Affiliated Hospital of the Harbin Medical University, Harbin, China.
authors: Xin
authors: X
authors: Gao
authors: 4 Animal Imaging Center, University of Pittsburgh, Pittsburgh, USA.
authors: Lesley M
authors: LM
authors: Foley
authors: 2 Department of Neurology, University of Pittsburgh, Pittsburgh, USA.
authors: Shaoxia
authors: S
authors: Wang
authors: 2 Department of Neurology, University of Pittsburgh, Pittsburgh, USA.
authors: Gulnaz
authors: G
authors: Begum
authors: 2 Department of Neurology, University of Pittsburgh, Pittsburgh, USA.
authors: Wen
authors: W
authors: Zhu
authors: 2 Department of Neurology, University of Pittsburgh, Pittsburgh, USA.
authors: Victoria M
authors: VM
authors: Pigott
authors: 2 Department of Neurology, University of Pittsburgh, Pittsburgh, USA.
authors: Lindsay M
authors: LM
authors: Falgoust
authors: 6 Department of Neurosurgery, Yale School of Medicine, New Haven, USA.|7 Department of Pediatrics, Yale School of Medicine, New Haven, USA.|8 Yale Program on Neurogenetics, Yale School of Medicine, New Haven, USA.
authors: Kristopher T
authors: KT
authors: Kahle
authors: 9 Division of Nephrology, Department of Medicine, Tri-Service General Hospital, Taipei, Taiwan.|10 Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
authors: Sung-Sen
authors: SS
authors: Yang
authors: 9 Division of Nephrology, Department of Medicine, Tri-Service General Hospital, Taipei, Taiwan.|10 Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
authors: Shih-Hua
authors: SH
authors: Lin
authors: 11 Division of Nephrology, Beth Israel Deaconess Medical Center, Boston, USA.|12 Department of Medicine, Harvard Medical School, Boston, USA.
authors: Seth L
authors: SL
authors: Alper
authors: 4 Animal Imaging Center, University of Pittsburgh, Pittsburgh, USA.|5 Department of Neurobiology, University of Pittsburgh, Pittsburgh, USA.
authors: T Kevin
authors: TK
authors: Hitchens
authors: 3 Department of Neurological Surgery, the Second Affiliated Hospital of the Harbin Medical University, Harbin, China.
authors: Shaoshan
authors: S
authors: Hu
authors: 1 Department of Neurology, the First Affiliated Hospital of the Harbin Medical University, Harbin, China.
authors: Zhongling
authors: Z
authors: Zhang
authors: 2 Department of Neurology, University of Pittsburgh, Pittsburgh, USA.
authors: Dandan
authors: D
authors: Sun
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D001929:Brain Edema / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000235:genetics* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D066127:White Matter / Q000378:metabolism / Q000473:pathology
chemical_list: C486407:Stk39 protein, mouse; D017346:Protein Serine-Threonine Kinases; C507511:Wnk3 protein, mouse
keywords: WNK3-SPAK; demyelination; edema; fractional anisotropy; magnetic resonance imaging