Poster Presentation ANZOS-Breakthrough Discoveries Joint Annual Scientific Meeting 2018

Complement C5a receptor 1 (C5aR1) modulates mitochondrial fatty acid oxidation and cardiolipin remodelling leading to diabetic kidney disease (#247)

Sih Min Tan 1 , Mark Ziemann 1 2 , Darren C Henstridge 3 , Peter J Meikle 3 , Sam El-Osta 1 , Elif I. Ekinci 4 5 , Trent Woodruff 6 , Melinda Coughlan 1
  1. Central Clinical School, Monash University, Melbourne, VIC, Australia
  2. School of Life and Environmental Sciences, Deakin University, Geelong, Victoria, Australia
  3. Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
  4. Department of Endocrinology, Austin Health, Melbourne, Victoria, Australia
  5. Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia
  6. School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia

The complement C5a-C5aR1 axis plays a crucial role in mediating inflammation in several inflammatory diseases. However, its role in diabetic kidney disease (DKD) is only beginning to be unravelled. Using an orally active inhibitor of C5aR1, PMX53, we aimed to investigate whether inhibition of the C5a-C5aR1 axis attenuates renal injury in streptozotocin (STZ)-induced diabetic mice.

Diabetes was induced in C57BL/6 mice by five daily injections of STZ (55mg/kg; n=6-12 mice/group). PMX53 (2mg/kg/day) was supplied in the drinking water for 24 weeks. Kidney function was assessed by urinary albumin and oxidative stress by urinary 8-isoprostane. Regulatory T cell (Treg, FoxP3 positive) were examined by immunohistochemistry. Plasma IL-18 was measured by ELISA. Glomerulosclerosis was assessed by glomerulosclerotic index scoring. RNA-Seq and lipidomics were performed on renal cortex.

Kidney dysfunction, assessed by albuminuria, was significantly attenuated in the diabetic mice treated with PMX53 (83±18 vs 30±9µg/24hr, p<0.05), along with a reduction in oxidative stress (urinary 8-isoprostane; 12±2 vs 4±1ng/24hr, p<0.01), inflammatory cytokine (plasma IL-18; 624±34 vs 440±60pg/24hr, p<0.05) and glomerulosclerosis (GSI; 2.8±0.1 vs 2.2±0.2). PMX53 also rescued the loss of anti-inflammatory FoxP3 positive Tregs in the diabetic kidneys (p<0.05). Transcriptomic profiling and lipidomics of the kidney in diabetes revealed downregulation of mitochondrial fatty acid metabolism (Acad10 and acylcarnitines). Interrogation of the lipidomics signature revealed abnormal cardiolipin remodelling in the diabetic kidney, a pivotal sign of disrupted mitochondrial bioenergetics and architecture. Blockade of C5aR1 signalling in diabetic mice normalized mitochondrial fatty acid metabolism and the cardiolipin signature, restoring mitochondrial homeostasis.

This study provides evidence for a pivotal role of the C5a/C5aR1 axis in propagating renal injury in the development of DKD via metabolic reprogramming and indicates that targeting this pathway may provide a substantial therapeutic benefit for this devastating complication of diabetes.