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dc.contributor.authorTan, Sih Min
dc.contributor.authorLindblom, Runa S. J.
dc.contributor.authorZiemann, Mark
dc.contributor.authorLaskowski, Adrienne
dc.contributor.authorGranata, Cesare
dc.contributor.authorSnelson, Matthew
dc.contributor.authorThallas-Bonke, Vicki
dc.contributor.authorEl-Osta, Assam
dc.contributor.authorBaeza-Garza, Carlos D.
dc.contributor.authorCaldwell, Stuart T.
dc.contributor.authorHartley, Richard C.
dc.contributor.authorKrieg, Thomas
dc.contributor.authorCooper, Mark E.
dc.contributor.authorMurphy, Michael P.
dc.contributor.authorCoughlan, Melinda T.
dc.date.accessioned2021-04-26T23:25:39Z
dc.date.available2021-04-26T23:25:39Z
dc.date.issued2021-04-25
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/321583
dc.description.abstractDiabetic kidney disease (DKD) remains the number one cause of end-stage renal disease in the western world. In experimental diabetes, mitochondrial dysfunction in the kidney precedes the development of DKD. Reactive 1,2-dicarbonyl compounds, such as methylglyoxal, are generated from sugars both endogenously during diabetes and exogenously during food processing. Methylglyoxal is thought to impair the mitochondrial function and may contribute to the pathogenesis of DKD. Here, we sought to target methylglyoxal within the mitochondria using MitoGamide, a mitochondria-targeted dicarbonyl scavenger, in an experimental model of diabetes. Male 6-week-old heterozygous Akita mice (C57BL/6-Ins2-Akita/J) or wildtype littermates were randomized to receive MitoGamide (10 mg/kg/day) or a vehicle by oral gavage for 16 weeks. MitoGamide did not alter the blood glucose control or body composition. Akita mice exhibited hallmarks of DKD including albuminuria, hyperfiltration, glomerulosclerosis, and renal fibrosis, however, after 16 weeks of treatment, MitoGamide did not substantially improve the renal phenotype. Complex-I-linked mitochondrial respiration was increased in the kidney of Akita mice which was unaffected by MitoGamide. Exploratory studies using transcriptomics identified that MitoGamide induced changes to olfactory signaling, immune system, respiratory electron transport, and post-translational protein modification pathways. These findings indicate that targeting methylglyoxal within the mitochondria using MitoGamide is not a valid therapeutic approach for DKD and that other mitochondrial targets or processes upstream should be the focus of therapy.
dc.languageen
dc.publisherMDPI
dc.subjectsugar-derived products
dc.subjectmethylglyoxal
dc.subjectdicarbonyl
dc.subjectdiabetes
dc.subjectkidney
dc.subjectmitochondria
dc.subjectMitoGamide
dc.titleTargeting Methylglyoxal in Diabetic Kidney Disease Using the Mitochondria-Targeted Compound MitoGamide
dc.typeArticle
dc.date.updated2021-04-26T23:25:38Z
prism.issueIdentifier5
prism.publicationNameNutrients
prism.volume13
dc.identifier.doi10.17863/CAM.68701
dcterms.dateAccepted2021-04-22
rioxxterms.versionofrecord10.3390/nu13051457
rioxxterms.versionVoR
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidLindblom, Runa S. J. [0000-0001-6755-8744]
dc.contributor.orcidGranata, Cesare [0000-0002-3509-6001]
dc.contributor.orcidSnelson, Matthew [0000-0003-4829-9550]
dc.contributor.orcidEl-Osta, Assam [0000-0001-7968-7375]
dc.contributor.orcidBaeza-Garza, Carlos D. [0000-0002-7423-4948]
dc.contributor.orcidKrieg, Thomas [0000-0002-5192-580X]
dc.contributor.orcidMurphy, Michael P. [0000-0003-1115-9618]
dc.contributor.orcidCoughlan, Melinda T. [0000-0001-8846-6443]
dc.identifier.eissn2072-6643
pubs.funder-project-idNational Health and Medical Research Council of Australia (GNT1101309)


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