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J Cereb Blood Flow Metab. 2017 Aug;37(8):2780-2794. doi: 10.1177/0271678X16675368. Epub 2016 Jan 1.

WNK-Cab39-NKCC1 signaling increases the susceptibility to ischemic brain damage in hypertensive rats.

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1 Department of Neurology, University of Pittsburgh, Pittsburgh, USA.
2 Department of Pathology, University of Pittsburgh, Pittsburgh, USA.
3 Department of Neurosurgery, Yale University School of Medicine, New Haven, USA.
4 Department of Pediatrics, Yale University School of Medicine, New Haven, USA.
5 Division of Nephrology, Department of Medicine, Tri-Service General Hospital, Taipei, Taiwan.
6 Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
7 Division of Nephrology and Vascular Biology Center, Beth Israel Deaconess Medical Center, Boston, USA.
8 Department of Medicine, Harvard Medical School, Boston, USA.
9 Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, USA.
10 Veterans Affairs Pittsburgh Health Care System, Geriatric Research, Educational and Clinical Center, Pittsburgh, USA.


With-no-lysine kinase (WNK) and Na+-K+-2Cl- cotransporter 1 (NKCC1) are involved in the pathogenesis of hypertension. In this study, we investigated the WNK-NKCC1 signaling pathway in spontaneously hypertensive rats (SHR) and their associated susceptibility to stroke injury. Basal NKCC1 protein levels were higher in SHR than in normotensive Wistar Kyoto (WKY) rat brains. After inducing ischemic stroke, adult male WKY and SHR received either saline or NKCC1 inhibitor bumetanide (10 mg/kg/day, i.p.) starting at 3-h post-reperfusion. NKCC1 inhibition blunted the extent of ischemic infarction in SHR and improved their neurobehavioral functions. Interestingly, ischemia led to increased NKCC1 phosphorylation in SHR but not in WKY rats. Pronounced elevation of WNK1, WNK2 and WNK4 protein and downregulation of WNK3 were detected in ischemic SHR, but not in ischemic WKY rats. Upregulation of WNK-NKCC1 complex in ischemic SHR brain was associated with increased Ca2+-binding protein 39 (Cab39), without increases in Ste20-related proline alanine-rich kinase or oxidative stress-responsive kinase-1. Moreover, subacute middle cerebral artery stroke human brain autopsy exhibited increased expression of NKCC1 protein. We conclude that augmented WNK-Cab39-NKCC1 signaling in SHR is associated with an increased susceptibility to ischemic brain damage and may serve as a novel target for anti-hypertensive and anti-ischemic stroke therapy.


Bumetanide; Cab39; NKCC1; SHR; WNK kinase; hypertension; ischemic stroke

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