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Abstract: SA-OR026

Inhibition of Complement C5a/C5a Receptor 1 Decreases Renal Injury in Diabetic Kidney Disease via Metabolic Reprogramming

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic


  • Coughlan, Melinda T., Monash University, Melbourne, Victoria, Australia
  • Tan, Sih Min, Monash University, Melbourne, Victoria, Australia
  • Ziemann, Mark, Monash University, Melbourne, Victoria, Australia
  • Woodruff, Trent M., The University of Queensland, St. Lucia, Queensland, Australia
  • Cooper, Mark E., Monash University, Melbourne, Victoria, Australia

Group or Team Name

  • Department of Diabetes

The complement system plays a central role in the activation of innate immunity, inflammation and tissue remodelling. The complement activation fragment C5a is a potent pro-inflammatory effector molecule. We have shown complement activation in patients with diabetes including renal deposition of the canonical C5a receptor C5aR1 and C5a/C5aR1 activation in experimental diabetes. This study aimed to determine whether genetic deletion or pharmacological inhibition of C5aR1 could confer renoprotection in diabetes.


Streptozotocin (STZ)-induced diabetic C57BL/6 mice were treated with the highly selective C5aR1 antagonist, PMX-53 (2mg/kg/day) in drinking water for 24 weeks (n=10). C5aR1 deficient mice (C5ar1-/-) and their wild type littermates were rendered diabetic with STZ and followed for 24 weeks (n=10). Kidney injury was assessed by urinary albumin excretion and glomerulosclerosis (GSI). Immunohistochemistry for Collagen IV, FoxP3+ regulatory T cells and F4/80+ cells was performed. Transcriptomics of renal cortex was performed by RNA-sequencing using the Illumina platform and pathway analyses using Gene Set Enrichment Analysis.


Diabetic C5ar1-/- mice showed protection against renal injury with decreased albumin excretion. Treatment of diabetic mice with PMX-53 led to a reduction in proteinuria, inhibition of glomerular injury and fibrosis and resolution of inflammation via a decrease in F4/80+ macrophages and activation of FoxP3+ regulatory T cells. Transcriptomic analyses showed that the diabetes gene signature was reversed by PMX-53. Pathways that were reduced by PMX-53 in diabetic mice were related to mitochondrial function and lipid metabolism. The top differential gene downregulated in the diabetic kidney was acyl-CoA dehydrogenase 10 (Acad-10), which participates in the beta-oxidation of fatty acids in mitochondria. Blockade of C5aR signalling in diabetic mice restored Acad-10 expression.


Our findings demonstrate that genetic or pharmacological disruption of C5aR1 is renoprotective in diabetes via restoration of pathways involved in fatty acid oxidation and by suppressing the pathogenic inflammatory response. This study indicates that targeting the C5a/C5aR1 pathway may provide a substantial therapeutic benefit for this devastating complication of diabetes.


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