RGD Reference Report - WNK-Cab39-NKCC1 signaling increases the susceptibility to ischemic brain damage in hypertensive rats. - Rat Genome Database
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WNK-Cab39-NKCC1 signaling increases the susceptibility to ischemic brain damage in hypertensive rats.

Authors: Bhuiyan, Mohammad Iqbal H  Song, Shanshan  Yuan, Hui  Begum, Gulnaz  Kofler, Julia  Kahle, Kristopher T  Yang, Sung-Sen  Lin, Shih-Hua  Alper, Seth L  Subramanya, Arohan R  Sun, Dandan 
Citation: Bhuiyan MIH, etal., J Cereb Blood Flow Metab. 2017 Aug;37(8):2780-2794. doi: 10.1177/0271678X16675368. Epub 2016 Jan 1.
RGD ID: 14398833
Pubmed: (View Article at PubMed) PMID:27798271
DOI: Full-text: DOI:10.1177/0271678X16675368

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.

Annotation

Disease Annotations    

Gene Ontology Annotations    

Cellular Component
cytosol  (IDA)
membrane  (IDA)

Objects Annotated

Genes (Rattus norvegicus)
Cab39  (calcium binding protein 39)
Slc12a2  (solute carrier family 12 member 2)
Wnk1  (WNK lysine deficient protein kinase 1)
Wnk2  (WNK lysine deficient protein kinase 2)
Wnk4  (WNK lysine deficient protein kinase 4)

Genes (Mus musculus)
Cab39  (calcium binding protein 39)
Slc12a2  (solute carrier family 12, member 2)
Wnk1  (WNK lysine deficient protein kinase 1)
Wnk2  (WNK lysine deficient protein kinase 2)
Wnk4  (WNK lysine deficient protein kinase 4)

Genes (Homo sapiens)
CAB39  (calcium binding protein 39)
SLC12A2  (solute carrier family 12 member 2)
WNK1  (WNK lysine deficient protein kinase 1)
WNK2  (WNK lysine deficient protein kinase 2)
WNK4  (WNK lysine deficient protein kinase 4)


Additional Information