Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/21916
Title: Complement C5a Induces Renal Injury in Diabetic Kidney Disease Via Disruption in Mitochondrial Metabolic Agility.
Austin Authors: Tan, Sih Min;Ziemann, Mark;Thallas-Bonke, Vicki;Snelson, Matthew;Kumar, Vinod;Laskowski, Adrienne;Nguyen, Tuong-Vi;Huynh, Kevin;Clarke, Michele V;Libianto, Renata;Baker, Scott T ;Skene, Alison ;Power, David A ;MacIsaac, Richard J;Henstridge, Darren C;Wetsel, Rick A;El-Osta, Assam;Meikle, Peter J;Wilson, Scott G;Forbes, Josephine M;Cooper, Mark E;Ekinci, Elif I ;Woodruff, Trent M;Coughlan, Melinda T
Affiliation: Research Center for Immunology and Autoimmune Diseases, Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas-Houston, Houston, TX, USA
Glycation and Diabetes Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia
Department of Anatomical Pathology, Austin Health, Heidelberg, Victoria, Australia
Department of Diabetes, Central Clinical School, Alfred Medical Research and Education Precinct, Monash University, Melbourne, Victoria, Australia
Deakin University, School of Life and Environmental Sciences, Geelong, Victoria, Australia
Department of Endocrinology, Austin Health, Heidelberg, Victoria, Australia
Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia
Department of Nephrology, Austin Health, Heidelberg, Victoria, Australia
Department of Endocrinology & Diabetes, St Vincent's Hospital, Melbourne, Victoria, Australia
Baker Heart & Diabetes Institute, Melbourne, Australia
Department of Renal Medicine, Alfred Health, Melbourne, Victoria, Australia
School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia
Institute for Breathing and Sleep, Austin Health, Heidelberg, Victoria, Australia
Issue Date: Jan-2020
metadata.dc.date: 2019-10-17
Publication information: Diabetes 2019; 69(1): 83-89
Abstract: The sequelae of diabetes mellitus include microvascular complications such as diabetic kidney disease (DKD), which involves glucose-mediated renal injury that is 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 which was not therapeutically targeted by conventional renoprotective agents. 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 remodelling in the diabetic kidney, 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 remodelling 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 studies provide evidence for a pivotal role of the C5a/C5aR1 axis in propagating renal injury in the development of DKD via disruption of mitochondrial agility, establishing a new immunometabolic signalling pathway in DKD.
URI: http://ahro.austin.org.au/austinjspui/handle/1/21916
DOI: 10.2337/db19-0043
ORCID: 0000-0003-3983-0581
0000-0003-2372-395X
0000-0003-4195-0523
0000-0001-8058-6977
0000-0002-5595-8174
0000-0001-8846-6443
PubMed URL: 31624141
Type: Journal Article
Appears in Collections:Journal articles

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