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dc.contributor.authorBeach, TEen
dc.contributor.authorPrag, Hiranen
dc.contributor.authorPala, Len
dc.contributor.authorLogan, Aen
dc.contributor.authorHuang, MMen
dc.contributor.authorGruszczyk, AVen
dc.contributor.authorMartin, JLen
dc.contributor.authorMahbubani, Krishnaaen
dc.contributor.authorHamed, MOen
dc.contributor.authorHosgood, Sarahen
dc.contributor.authorNicholson, Michaelen
dc.contributor.authorJames, Andrewen
dc.contributor.authorHartley, RCen
dc.contributor.authorMurphy, Mikeen
dc.contributor.authorSaeb-Parsy, Kouroshen
dc.date.accessioned2020-07-29T23:31:08Z
dc.date.available2020-07-29T23:31:08Z
dc.date.issued2020-09-01en
dc.identifier.issn2213-2317
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/308586
dc.description.abstractRenal ischemia reperfusion (IR) injury leads to significant patient morbidity and mortality, and its amelioration is an urgent unmet clinical need. Succinate accumulates during ischemia and its oxidation by the mitochondrial enzyme succinate dehydrogenase (SDH) drives the ROS production that underlies IR injury. Consequently, compounds that inhibit SDH may have therapeutic potential against renal IR injury. Among these, the competitive SDH inhibitor malonate, administered as a cell-permeable malonate ester prodrug, has shown promise in models of cardiac IR injury, but the efficacy of malonate ester prodrugs against renal IR injury have not been investigated. Here we show that succinate accumulates during ischemia in mouse, pig and human models of renal IR injury, and that its rapid oxidation by SDH upon reperfusion drives IR injury. We then show that the malonate ester prodrug, dimethyl malonate (DMM), can ameliorate renal IR injury when administered at reperfusion but not prior to ischemia in the mouse. Finally, we show that another malonate ester prodrug, diacetoxymethyl malonate (MAM), is more potent than DMM because of its faster esterase hydrolysis. Our data show that the mitochondrial mechanisms of renal IR injury are conserved in the mouse, pig and human and that inhibition of SDH by ‘tuned’ malonate ester prodrugs, such as MAM, is a promising therapeutic strategy in the treatment of clinical renal IR injury.
dc.publisherElsevier
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.titleTargeting succinate dehydrogenase with malonate ester prodrugs decreases renal ischemia reperfusion injuryen
dc.typeArticle
prism.publicationDate2020en
prism.publicationNameRedox Biologyen
prism.volume36en
dc.identifier.doi10.17863/CAM.55673
dcterms.dateAccepted2020-07-06en
rioxxterms.versionofrecord10.1016/j.redox.2020.101640en
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2020-09-01en
dc.contributor.orcidPrag, Hiran [0000-0002-4753-8567]
dc.contributor.orcidMahbubani, Krishnaa [0000-0002-1327-2334]
dc.contributor.orcidHosgood, Sarah [0000-0002-8039-143X]
dc.contributor.orcidNicholson, Michael [0000-0001-7620-0664]
dc.contributor.orcidMurphy, Mike [0000-0003-1115-9618]
dc.contributor.orcidSaeb-Parsy, Kourosh [0000-0002-0633-3696]
dc.identifier.eissn2213-2317
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idMRC (MC_U105663142)
pubs.funder-project-idWellcome Trust (110159/Z/15/Z)
pubs.funder-project-idMRC (MC_UU_00015/3)
cam.issuedOnline2020-07-12en


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International