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dc.contributor.authorTan, SM
dc.contributor.authorZiemann, M
dc.contributor.authorThallas-Bonke, V
dc.contributor.authorSnelson, M
dc.contributor.authorKumar, V
dc.contributor.authorLaskowski, A
dc.contributor.authorNguyen, T-V
dc.contributor.authorHuynh, K
dc.contributor.authorClarke, MV
dc.contributor.authorLibianto, R
dc.contributor.authorBaker, ST
dc.contributor.authorSkene, A
dc.contributor.authorPower, DA
dc.contributor.authorMacIsaac, RJ
dc.contributor.authorHenstridge, DC
dc.contributor.authorWetsel, RA
dc.contributor.authorEl-Osta, A
dc.contributor.authorMeikle, PJ
dc.contributor.authorWilson, SG
dc.contributor.authorForbes, JM
dc.contributor.authorCooper, ME
dc.contributor.authorEkinci, EI
dc.contributor.authorWoodruff, TM
dc.contributor.authorCoughlan, MT
dc.identifierpii: db19-0043
dc.identifier.citationTan, S. M., Ziemann, M., Thallas-Bonke, V., Snelson, M., Kumar, V., Laskowski, A., Nguyen, T. -V., Huynh, K., Clarke, M. V., Libianto, R., Baker, S. T., Skene, A., Power, D. A., MacIsaac, R. J., Henstridge, D. C., Wetsel, R. A., El-Osta, A., Meikle, P. J., Wilson, S. G. ,... Coughlan, M. T. (2020). Complement C5a Induces Renal Injury in Diabetic Kidney Disease by Disrupting Mitochondrial Metabolic Agility. DIABETES, 69 (1), pp.83-98.
dc.description.abstractThe sequelae of diabetes include microvascular complications such as diabetic kidney disease (DKD), which involves glucose-mediated renal injury associated with a disruption in mitochondrial metabolic agility, inflammation, and fibrosis. We explored the role of the innate immune complement component C5a, a potent mediator of inflammation, in the pathogenesis of DKD in clinical and experimental diabetes. Marked systemic elevation in C5a activity was demonstrated in patients with diabetes; conventional renoprotective agents did not therapeutically target this elevation. C5a and its receptor (C5aR1) were upregulated early in the disease process and prior to manifest kidney injury in several diverse rodent models of diabetes. Genetic deletion of C5aR1 in mice conferred protection against diabetes-induced renal injury. Transcriptomic profiling of kidney revealed diabetes-induced downregulation of pathways involved in mitochondrial fatty acid metabolism. Interrogation of the lipidomics signature revealed abnormal cardiolipin remodeling in diabetic kidneys, a cardinal sign of disrupted mitochondrial architecture and bioenergetics. In vivo delivery of an orally active inhibitor of C5aR1 (PMX53) reversed the phenotypic changes and normalized the renal mitochondrial fatty acid profile, cardiolipin remodeling, and citric acid cycle intermediates. In vitro exposure of human renal proximal tubular epithelial cells to C5a led to altered mitochondrial respiratory function and reactive oxygen species generation. These experiments provide evidence for a pivotal role of the C5a/C5aR1 axis in propagating renal injury in the development of DKD by disrupting mitochondrial agility, thereby establishing a new immunometabolic signaling pathway in DKD.
dc.titleComplement C5a Induces Renal Injury in Diabetic Kidney Disease by Disrupting Mitochondrial Metabolic Agility
dc.typeJournal Article
melbourne.affiliation.departmentMicrobiology and Immunology
melbourne.affiliation.departmentMedicine and Radiology
melbourne.affiliation.departmentClinical School (Austin Health)
melbourne.affiliation.departmentUniversity General
melbourne.affiliation.departmentClinical Pathology
melbourne.affiliation.departmentResearch, Innovation and Commercialisation
melbourne.affiliation.departmentClinical School (Royal Melbourne Hospital)
melbourne.openaccess.statusAccepted version
melbourne.contributor.authorLibianto, Renata
melbourne.contributor.authorMacIsaac, Richard
melbourne.contributor.authorPower, David
melbourne.contributor.authorTAN, SIH
melbourne.contributor.authorZiemann, Mark
melbourne.contributor.authorThallas, Vicki
melbourne.contributor.authorClarke, Michele
melbourne.contributor.authorBAKER, SCOTT
melbourne.contributor.authorSkene, Alison
melbourne.contributor.authorHenstridge, Darren
melbourne.contributor.authorEl-Osta, Assam
melbourne.contributor.authorMeikle, Peter
melbourne.contributor.authorNGUYEN, TUONG-VI THI
melbourne.contributor.authorWILSON, SCOTT
melbourne.contributor.authorFORBES, JOSEPHINE
melbourne.contributor.authorCOOPER, MARK
melbourne.contributor.authorEkinci, Elif
melbourne.contributor.authorCOUGHLAN, MELINDA THERESE
melbourne.contributor.authorHuynh, Kevin
melbourne.accessrightsAccess this item via the Open Access location

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