Complement C5a Induces Renal Injury in Diabetic Kidney Disease by Disrupting Mitochondrial Metabolic Agility

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.

Complement C5 activation promotes type 2 diabetic kidney disease via activating STAT3 pathway and disrupting the gut‐kidney axis

“…DKD is one of the major causes of morbidity and mortality in diabetic patients, and inappropriate activation of the complement system has been implicated in diabetes and renal diseases 24 . The plasma levels of C5a are markedly elevated in normoalbuminuric patients with diabetes compared to non‐diabetic controls 25 . In renal samples from patients with DKD, the complement system has been identified as one of the most significantly regulated pathways, 26 and activation of the complement system contributes to the progression of DKD 27 .…”

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“…11,12 With chronic and diabetic kidney diseases, TCA cycle was disrupted, which may be caused by mitochondrial dysfunction. 42,43 In this study, the increased level of citrate, and aconitate in the recovered COVID-19 patients indicated their mitochondrial function may not restore to normal. Pantothenate, the precursor of coenzyme A (CoA), can slow cell injury and apoptosis and promote cell repair by increasing glutathione biosynthesis, or resistance to lipid peroxidation by forming CoA.…”

Valproic acid influences the expression of genes implicated with hyperglycaemia-induced complement and coagulation pathways

“…MASP-1 and MASP-2 levels were significantly higher in children and adults with T1DM than in their respective control groups, whereas these proteins levels decreased when glycemic control improved 57 . In a recent study it was reported that in a murine model of diabetic nephropathy, genetic knock-out or pharmacological blockade of complement component 5a receptor 1 (C5ar1) conferred renal protection and attenuated disease-associated metabolic changes, further reinforcing the importance of the complement pathway 58 .…”