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.
Tan S, Ziemann M, Thallas-Bonke V, Snelson M, Baker S, Jerums G, Skene A, Power D, MacIsaac R, Henstridge D, Wetsel R, Meikle P, El-Osta A, Forbes J, Cooper M, Ekinci E, Woodruff T, Coughlan M: Complement C5a Induces Renal Injury in Diabetic Kidney Disease Via Disruption in Mitochondrial Metabolic Agility Diabetes, Volume 69, Issue 1, 2020, Pages 83-98