Evidence map›Paper›PMID 26069258›Full record

ArticleStroke2015

Inhibition of WNK3 Kinase Signaling Reduces Brain Damage and Accelerates Neurological Recovery After Stroke.

Gulnaz Begum, Hui Yuan, Kristopher T Kahle, Liaoliao Li, Shaoxia Wang, Yejie Shi, Boris E Shmukler, Sung-Sen Yang, Shih-Hua Lin, Seth L Alper and 1 more

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PubMed Full text at PMC Publisher
In one paragraph

Article in Stroke, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 64 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
64citing papers in PubMed, 1 pooled it
11.0field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

64 citing papers in PubMed, 1 synthesis or guideline pooled it, 108 citations in OpenAlex.

  1. Pooled it
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  9. Mechanisms of hydrocephalus after intraventricular haemorrhage: a review.Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery · 2024
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4 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors at 3 institutions in 2 countries.

Gulnaz Begum *Department of Neurology, University of Pittsburgh, Pittsburgh, PA, (G.B., H.Y., L.L., S.W., Y.S., D.S.); Department of Neurosurgery, Boston Children's Hospital and Harvard Medical School, Boston, MA (K.T.K.); Manton Center for Orphan Diseases, Harvard Medical School, MA (K.T.K.); Renal Division and Vascular Biology Center, Beth Israel Deaconess Medical Center, and Department of Medicine, Harvard Medical School, Boston, MA (B.E.S., S.L.A); Division of Nephrology, Dept. of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (SS.Y., SH.L); Veterans Affairs Pittsburgh Health Care System, Geriatric Research, Educational and Clinical Center, Pittsburgh, PA (D.S).
Hui Yuan *Department of Neurology, University of Pittsburgh, Pittsburgh, PA, (G.B., H.Y., L.L., S.W., Y.S., D.S.); Department of Neurosurgery, Boston Children's Hospital and Harvard Medical School, Boston, MA (K.T.K.); Manton Center for Orphan Diseases, Harvard Medical School, MA (K.T.K.); Renal Division and Vascular Biology Center, Beth Israel Deaconess Medical Center, and Department of Medicine, Harvard Medical School, Boston, MA (B.E.S., S.L.A); Division of Nephrology, Dept. of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (SS.Y., SH.L); Veterans Affairs Pittsburgh Health Care System, Geriatric Research, Educational and Clinical Center, Pittsburgh, PA (D.S).
Kristopher T Kahle *Department of Neurology, University of Pittsburgh, Pittsburgh, PA, (G.B., H.Y., L.L., S.W., Y.S., D.S.); Department of Neurosurgery, Boston Children's Hospital and Harvard Medical School, Boston, MA (K.T.K.); Manton Center for Orphan Diseases, Harvard Medical School, MA (K.T.K.); Renal Division and Vascular Biology Center, Beth Israel Deaconess Medical Center, and Department of Medicine, Harvard Medical School, Boston, MA (B.E.S., S.L.A); Division of Nephrology, Dept. of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (SS.Y., SH.L); Veterans Affairs Pittsburgh Health Care System, Geriatric Research, Educational and Clinical Center, Pittsburgh, PA (D.S).
Liaoliao LiDepartment of Neurology, University of Pittsburgh, Pittsburgh, PA, (G.B., H.Y., L.L., S.W., Y.S., D.S.); Department of Neurosurgery, Boston Children's Hospital and Harvard Medical School, Boston, MA (K.T.K.); Manton Center for Orphan Diseases, Harvard Medical School, MA (K.T.K.); Renal Division and Vascular Biology Center, Beth Israel Deaconess Medical Center, and Department of Medicine, Harvard Medical School, Boston, MA (B.E.S., S.L.A); Division of Nephrology, Dept. of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (SS.Y., SH.L); Veterans Affairs Pittsburgh Health Care System, Geriatric Research, Educational and Clinical Center, Pittsburgh, PA (D.S).
Shaoxia WangDepartment of Neurology, University of Pittsburgh, Pittsburgh, PA, (G.B., H.Y., L.L., S.W., Y.S., D.S.); Department of Neurosurgery, Boston Children's Hospital and Harvard Medical School, Boston, MA (K.T.K.); Manton Center for Orphan Diseases, Harvard Medical School, MA (K.T.K.); Renal Division and Vascular Biology Center, Beth Israel Deaconess Medical Center, and Department of Medicine, Harvard Medical School, Boston, MA (B.E.S., S.L.A); Division of Nephrology, Dept. of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (SS.Y., SH.L); Veterans Affairs Pittsburgh Health Care System, Geriatric Research, Educational and Clinical Center, Pittsburgh, PA (D.S).
Yejie ShiDepartment of Neurology, University of Pittsburgh, Pittsburgh, PA, (G.B., H.Y., L.L., S.W., Y.S., D.S.); Department of Neurosurgery, Boston Children's Hospital and Harvard Medical School, Boston, MA (K.T.K.); Manton Center for Orphan Diseases, Harvard Medical School, MA (K.T.K.); Renal Division and Vascular Biology Center, Beth Israel Deaconess Medical Center, and Department of Medicine, Harvard Medical School, Boston, MA (B.E.S., S.L.A); Division of Nephrology, Dept. of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (SS.Y., SH.L); Veterans Affairs Pittsburgh Health Care System, Geriatric Research, Educational and Clinical Center, Pittsburgh, PA (D.S).
Boris E ShmuklerDepartment of Neurology, University of Pittsburgh, Pittsburgh, PA, (G.B., H.Y., L.L., S.W., Y.S., D.S.); Department of Neurosurgery, Boston Children's Hospital and Harvard Medical School, Boston, MA (K.T.K.); Manton Center for Orphan Diseases, Harvard Medical School, MA (K.T.K.); Renal Division and Vascular Biology Center, Beth Israel Deaconess Medical Center, and Department of Medicine, Harvard Medical School, Boston, MA (B.E.S., S.L.A); Division of Nephrology, Dept. of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (SS.Y., SH.L); Veterans Affairs Pittsburgh Health Care System, Geriatric Research, Educational and Clinical Center, Pittsburgh, PA (D.S).
Sung-Sen YangDepartment of Neurology, University of Pittsburgh, Pittsburgh, PA, (G.B., H.Y., L.L., S.W., Y.S., D.S.); Department of Neurosurgery, Boston Children's Hospital and Harvard Medical School, Boston, MA (K.T.K.); Manton Center for Orphan Diseases, Harvard Medical School, MA (K.T.K.); Renal Division and Vascular Biology Center, Beth Israel Deaconess Medical Center, and Department of Medicine, Harvard Medical School, Boston, MA (B.E.S., S.L.A); Division of Nephrology, Dept. of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (SS.Y., SH.L); Veterans Affairs Pittsburgh Health Care System, Geriatric Research, Educational and Clinical Center, Pittsburgh, PA (D.S).
Shih-Hua LinDepartment of Neurology, University of Pittsburgh, Pittsburgh, PA, (G.B., H.Y., L.L., S.W., Y.S., D.S.); Department of Neurosurgery, Boston Children's Hospital and Harvard Medical School, Boston, MA (K.T.K.); Manton Center for Orphan Diseases, Harvard Medical School, MA (K.T.K.); Renal Division and Vascular Biology Center, Beth Israel Deaconess Medical Center, and Department of Medicine, Harvard Medical School, Boston, MA (B.E.S., S.L.A); Division of Nephrology, Dept. of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (SS.Y., SH.L); Veterans Affairs Pittsburgh Health Care System, Geriatric Research, Educational and Clinical Center, Pittsburgh, PA (D.S).
Seth L AlperDepartment of Neurology, University of Pittsburgh, Pittsburgh, PA, (G.B., H.Y., L.L., S.W., Y.S., D.S.); Department of Neurosurgery, Boston Children's Hospital and Harvard Medical School, Boston, MA (K.T.K.); Manton Center for Orphan Diseases, Harvard Medical School, MA (K.T.K.); Renal Division and Vascular Biology Center, Beth Israel Deaconess Medical Center, and Department of Medicine, Harvard Medical School, Boston, MA (B.E.S., S.L.A); Division of Nephrology, Dept. of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (SS.Y., SH.L); Veterans Affairs Pittsburgh Health Care System, Geriatric Research, Educational and Clinical Center, Pittsburgh, PA (D.S).
Dandan SunDepartment of Neurology, University of Pittsburgh, Pittsburgh, PA, (G.B., H.Y., L.L., S.W., Y.S., D.S.); Department of Neurosurgery, Boston Children's Hospital and Harvard Medical School, Boston, MA (K.T.K.); Manton Center for Orphan Diseases, Harvard Medical School, MA (K.T.K.); Renal Division and Vascular Biology Center, Beth Israel Deaconess Medical Center, and Department of Medicine, Harvard Medical School, Boston, MA (B.E.S., S.L.A); Division of Nephrology, Dept. of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (SS.Y., SH.L); Veterans Affairs Pittsburgh Health Care System, Geriatric Research, Educational and Clinical Center, Pittsburgh, PA (D.S).
Beth Israel Deaconess Medical Center · USNational Defense Medical Center · TWTri-Service General Hospital · TW

Funding

Na-K-Cl Contransporter in Cerebral IschemiaR01NS038118 · NINDS · UNIVERSITY OF WISCONSIN-MADISON · PI SUN, DANDAN · 2000 to 2018
$5.0M
INSTITUTIONAL SHORT TERM TRAINING FOR MINORITY STUDENTST35HL007765 · NHLBI · STATE UNIVERSITY OF NEW YORK AT BUFFALO · PI MORIN, FREDERICK CLEMENT · 1992 to 2006
$613k
NHLBI NIH HHS T35 HL007765NINDS NIH HHS R01 NS038118
6 · The paper itself

Abstract

background and purposeWNK kinases, including WNK3, and the associated downstream Ste20/SPS1-related proline-alanine-rich protein kinase (SPAK) and oxidative stress responsive 1 (OSR1) kinases, comprise an important signaling cascade that regulates the cation-chloride cotransporters. Ischemia-induced stimulation of the bumetanide-sensitive Na(+)-K(+)-Cl(-) cotransporter (NKCC1) plays an important role in the pathophysiology of experimental stroke, but the mechanism of its regulation in this context is unknown. Here, we investigated the WNK3-SPAK/OSR1 pathway as a regulator of NKCC1 stimulation and their collective role in ischemic brain damage.

methodWild-type WNK3 and WNK3 knockout mice were subjected to ischemic stroke via transient middle cerebral artery occlusion. Infarct volume, brain edema, blood brain barrier damage, white matter demyelination, and neurological deficits were assessed. Total and phosphorylated forms of WNK3 and SPAK/OSR1 were assayed by immunoblotting and immunostaining. In vitro ischemia studies in cultured neurons and immature oligodendrocytes were conducted using the oxygen-glucose deprivation/reoxygenation method.

resultsWNK3 knockout mice exhibited significantly decreased infarct volume and axonal demyelination, less cerebral edema, and accelerated neurobehavioral recovery compared with WNK3 wild-type mice subjected to middle cerebral artery occlusion. The neuroprotective phenotypes conferred by WNK3 knockout were associated with a decrease in stimulatory hyperphosphorylations of the SPAK/OSR1 catalytic T-loop and of NKCC1 stimulatory sites Thr(203)/Thr(207)/Thr(212), as well as with decreased cell surface expression of NKCC1. Genetic inhibition of WNK3 or small interfering RNA knockdown of SPAK/OSR1 increased the tolerance of cultured primary neurons and oligodendrocytes to in vitro ischemia.

conclusionsThese data identify a novel role for the WNK3-SPAK/OSR1-NKCC1 signaling pathway in ischemic neuroglial injury and suggest the WNK3-SPAK/OSR1 kinase pathway as a therapeutic target for neuroprotection after ischemic stroke.

Indexed as

Recovery of FunctionAnimalsBrain InjuriesCells, CulturedFemaleMaleMiceMice, 129 StrainMice, KnockoutMice, TransgenicNervous System DiseasesPregnancyProtein Serine-Threonine KinasesSignal TransductionStrokeProtein Serine-Threonine KinasesWnk3 protein, mousebumetanideKCC2 cotransporterNKCC1 cotransporterOSR1 kinaseSPAK Kinase

Identifiers

PMID26069258
PMCPMC4643659
OpenAlexW1822076535

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.