DUAL INHIBITION OF COMPLEMENT C5a RECEPTOR 1 AND 2 IN DIABETIC KIDNEY DISEASE
Dr Sih Min Tan1, Inez Trambas1, Adrienne Laskowski1, Amalia Khayyira1, Arpeeta Sharma1, Trent Woodruff2, Melinda Coughlan1
1Department of Diabetes, School of Translational Medicine, Monash University, Melbourne, Australia, 2School of Biomedical Sciences, Faculty of Medicine, University of Queensland, St Lucia, Australia
Aim: To ascertain if dual inhibition of C5aR1 and C5aR2 is renoprotective in a mouse model of diabetic kidney disease (DKD).
Background: Complement anaphylatoxin C5a is a potent inflammatory mediator. We have shown that inhibition of its receptor, C5aR1, either by genetic deletion or pharmacological inhibition is renoprotective in streptozotocin-induced diabetic mice. However, C5a also signals through a second receptor, C5aR2, with equal potency. The enigmatic C5aR2 is thought to be a nonsignalling decoy receptor for C5aR1, and its role in DKD is currently unclear. To ascertain the role of both receptors in DKD, we assessed renal function and injury in streptozotocin-induced diabetic C5aR1/C5aR2 double knockout (DKO) mice.
Methods: WT and DKO mice were treated with five daily injections of low dose streptozotocin (55mg/kg) to induce diabetes and followed for 10 weeks. 24hr urine was collected for the measurement of albuminuria. Immune phenotyping was performed with spectral flow cytometry. Mitochondrial function was assessed by Seahorse bioanalyzer.
Results: Diabetes induced an increase in kidney weight, albuminuria, blood glucose, HbA1c, water intake and urine output (P<0.01) in both WT and DKO mice. Interestingly, DKO mice displayed an overall reduction in mitochondrial oxygen consumption rate. However, mitochondrial maximal respiration capacity was increased in diabetic DKO mice when compared to nondiabetic DKO (P<0.01), but this increase was not found in the WT kidney. Furthermore, anti-inflammatory FoxP3+ regulatory T cells were increased in nondiabetic DKO mice when compared to WT (P<0.05) but not in the diabetic DKO group.
Conclusions: Overall, although the function of C5a receptors in DKD is still unclear, dual targeting of both C5a receptors suggest an immunomodulatory effect without affecting kidney function or glucose homeostasis.
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Biography:
Dr Tan is a senior research fellow at the Department of Diabetes, Monash University. Her research program focuses on the role of the complement system in diabetic kidney disease. She was awarded a NHMRC Ideas Grant in 2022 to investigate the role of the complement C5a receptors in diabetic kidney disease. She was a previous holder of a JDRF International Postdoctoral Fellowship and a JDRF International Advanced Postdoctoral Fellowship.