Targeting the C5a-C5aR1 Signalling Axis in Diabetic Nephropathy — ASN Events
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  3. Targeting the C5a-C5aR1 Signalling Axis in Diabetic Nephropathy

Targeting the C5a-C5aR1 Signalling Axis in Diabetic Nephropathy (#13)

Sih Min Tan 1 , Vicki Bonke 1 , Alison Skene 2 , David Power 2 , Richard MacIsaac , Elif I. Ekinci 3 , Mark Cooper 4 , Trent Woodruff 5 , Melinda T Coughlan 1
  1. Glycation, Nutrition & Metabolism Laboratory, Baker IDI Heart & Diabetes Institute, Melbourne, VIC, Australia
  2. Austin Health, Melbourne
  3. The University of Melbourne, Melbourne, VIC, Australia
  4. Baker IDI Heart & Diabetes Institute, Melbourne, Vic, Australia
  5. Laboratory for Neuroinflammation, The University of Queensland, Brisbane, QLD

Background

Complement 5a is a potent pro-inflammatory effector molecule. The role of C5a and its receptor C5aR1 in mediating kidney injury in DN has yet to be determined. The aim of this study was to investigate the pathogenic role of C5a-C5aR1 signaling in DN and to ascertain whether blockade of this pathway is renoprotective.

Methods

The spontaneously diabetic Ins2-Akita mouse model was used to characterise the changes in complement activation products associated with DN (n=8 mice/group, 26 weeks of age). Blockade of the C5a-C5aR1 signaling axis was achieved by using the highly selective and potent C5aR1 antagonist, AcF-[OPdChaWR] (PMX53), in streptozotocin (STZ)-induced diabetic mice (2mg/kg/day, drinking water, 24 weeks, n=6-15 per group). C5aR1 gene expression was measured by qRT-PCR and protein by immunohistochemistry. Urinary C5a and albumin were measured by ELISA. Glomerulosclerosis was examined by Periodic Acid Schiff (PAS) staining. C5aR1 was determined in human renal biopsies obtained from patients with DN (n=23) compared to healthy donor kidneys (n=6) by immunohistochemistry.

Results

C5aR1 was increased in renal biopsies from patients with DN compared to donor kidneys (5.1±1.9 vs 15.7±1.8%, p<0.001). C5aR1 expression was upregulated in the renal cortex of Ins2-Akita mice (1.0±0.1 vs 1.4±0.1 fold change; p<0.05) compared to non-diabetic controls. Urinary C5a was increased in Ins2-Akita mice (43±7 vs 151±32pg/24hr, p<0.001), and these increases were associated with albuminuria. Compared to vehicle-treated diabetic controls, blockade of C5aR1 signalling with PMX53 resulted in a reduction in urinary C5a in STZ-induced diabetic mice (315±100 vs 49.1±7.6pg/24hr, p<0.001), albuminuria (247±30 vs 74±28µg/24hr; p<0.001) and glomerulosclerosis (20.2±0.7 vs 15.0±0.4 % PAS-stained area/gcs; p<0.0001).

Conclusions

The C5a-C5aR signaling axis is activated in human and experimental DN. A pilot study using PMX53 indicates that blockade of C5a-C5aR signaling is renoprotective in DN. Further studies are required to validate C5aR as a therapeutic target in DN.

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