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J Cereb Blood Flow Metab. 2017 Feb;37(2):550-563. doi: 10.1177/0271678X16631561. Epub 2016 Jul 20.

Deletion of the WNK3-SPAK kinase complex in mice improves radiographic and clinical outcomes in malignant cerebral edema after ischemic stroke.

Author information

1
1 Department of Neurology, the First Affiliated Hospital of the Harbin Medical University, Harbin, China.
2
2 Department of Neurology, University of Pittsburgh, Pittsburgh, USA.
3
3 Department of Neurological Surgery, the Second Affiliated Hospital of the Harbin Medical University, Harbin, China.
4
4 Animal Imaging Center, University of Pittsburgh, Pittsburgh, USA.
5
6 Department of Neurosurgery, Yale School of Medicine, New Haven, USA.
6
7 Department of Pediatrics, Yale School of Medicine, New Haven, USA.
7
8 Yale Program on Neurogenetics, Yale School of Medicine, New Haven, USA.
8
9 Division of Nephrology, Department of Medicine, Tri-Service General Hospital, Taipei, Taiwan.
9
10 Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
10
11 Division of Nephrology, Beth Israel Deaconess Medical Center, Boston, USA.
11
12 Department of Medicine, Harvard Medical School, Boston, USA.
12
5 Department of Neurobiology, University of Pittsburgh, Pittsburgh, USA.

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.

KEYWORDS:

WNK3-SPAK; demyelination; edema; fractional anisotropy; magnetic resonance imaging

PMID:
26861815
PMCID:
PMC5381450
DOI:
10.1177/0271678X16631561
[Indexed for MEDLINE]
Free PMC Article

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