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dc.contributor.authorKishi, Seijien_US
dc.contributor.authorCampanholle, Gabrielaen_US
dc.contributor.authorGohil, Vishal M.en_US
dc.contributor.authorPerocchi, Fabianaen_US
dc.contributor.authorBrooks, Craig R.en_US
dc.contributor.authorMorizane, Ryujien_US
dc.contributor.authorSabbisetti, Venkataen_US
dc.contributor.authorIchimura, Takaharuen_US
dc.contributor.authorMootha, Vamsi K.en_US
dc.contributor.authorBonventre, Joseph V.en_US
dc.date.accessioned2015-11-03T15:57:39Z
dc.date.issued2015en_US
dc.identifier.citationKishi, Seiji, Gabriela Campanholle, Vishal M. Gohil, Fabiana Perocchi, Craig R. Brooks, Ryuji Morizane, Venkata Sabbisetti, Takaharu Ichimura, Vamsi K. Mootha, and Joseph V. Bonventre. 2015. “Meclizine Preconditioning Protects the Kidney Against Ischemia–Reperfusion Injury.” EBioMedicine 2 (9): 1090-1101. doi:10.1016/j.ebiom.2015.07.035. http://dx.doi.org/10.1016/j.ebiom.2015.07.035.en
dc.identifier.issn2352-3964en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:23473900
dc.description.abstractGlobal or local ischemia contributes to the pathogenesis of acute kidney injury (AKI). Currently there are no specific therapies to prevent AKI. Potentiation of glycolytic metabolism and attenuation of mitochondrial respiration may decrease cell injury and reduce reactive oxygen species generation from the mitochondria. Meclizine, an over-the-counter anti-nausea and -dizziness drug, was identified in a ‘nutrient-sensitized’ chemical screen. Pretreatment with 100 mg/kg of meclizine, 17 h prior to ischemia protected mice from IRI. Serum creatinine levels at 24 h after IRI were 0.13 ± 0.06 mg/dl (sham, n = 3), 1.59 ± 0.10 mg/dl (vehicle, n = 8) and 0.89 ± 0.11 mg/dl (meclizine, n = 8). Kidney injury was significantly decreased in meclizine treated mice compared with vehicle group (p < 0.001). Protection was also seen when meclizine was administered 24 h prior to ischemia. Meclizine reduced inflammation, mitochondrial oxygen consumption, oxidative stress, mitochondrial fragmentation, and tubular injury. Meclizine preconditioned kidney tubular epithelial cells, exposed to blockade of glycolytic and oxidative metabolism with 2-deoxyglucose and NaCN, had reduced LDH and cytochrome c release. Meclizine upregulated glycolysis in glucose-containing media and reduced cellular ATP levels in galactose-containing media. Meclizine inhibited the Kennedy pathway and caused rapid accumulation of phosphoethanolamine. Phosphoethanolamine recapitulated meclizine-induced protection both in vitro and in vivo.en
dc.language.isoen_USen
dc.publisherElsevieren
dc.relation.isversionofdoi:10.1016/j.ebiom.2015.07.035en
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4588407/pdf/en
dash.licenseLAAen_US
dc.subjectAcute kidney injuryen
dc.subjectMitochondriaen
dc.subjectPhosphoethanolamineen
dc.subjectKennedy pathwayen
dc.subjectGlycolysisen
dc.subjectOxidative phosphorylationen
dc.titleMeclizine Preconditioning Protects the Kidney Against Ischemia–Reperfusion Injuryen
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden
dc.relation.journalEBioMedicineen
dash.depositing.authorBrooks, Craig R.en_US
dc.date.available2015-11-03T15:57:39Z
dc.identifier.doi10.1016/j.ebiom.2015.07.035*
dash.contributor.affiliatedBrooks, Craig R.
dash.contributor.affiliatedMorizane, Ryuji
dash.contributor.affiliatedIchimura, Takaharu
dash.contributor.affiliatedSabbisetti, Venkata
dash.contributor.affiliatedBonventre, Joseph
dash.contributor.affiliatedMootha, Vamsi


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