Transcriptional regulation and therapeutic targeting of P2X7 receptors in diabetic nephropathy

Abstract

Purine P2X7 receptors are essential components of pro‐inflammatory signalling, functionally expressed on multiple immune and non‐immune cells. Renal biopsies from patients with diabetic nephropathy show widespread, glomerular mesangial expansion, immune cell infiltration and fibrosis. Here we show that in diabetic patients, renal P2X7 expression is associated with severe mesangial expansion, impaired glomerular filtration (≥40ml/min), and increased fibrosis (50%+) compared with non‐diabetic controls. P2rx7‐deficient mice developed STZ‐induced hyperglycaemia similar to controls but had reduced glomerular macrophage attraction and collagen IV deposition. Activation of P2X7 was investigated in a rat model of diabetic nephropathy. Wister rats underwent uninephrectomy and STZ‐induction. Whole kidney P2rx7 mRNA expression was increased (2.2‐fold; P<0.05) compared with sham controls by 8 weeks of induction. Glomerular and interstitial macrophage accrual increased, reflecting the pathology seen in patient biopsies. Rats were then randomly selected to receive drug vehicle or selective P2X7R antagonist (AZ11657312; 50mg/kg IP) twice daily for the following 4‐weeks. P2X7R antagonism supressed transcription of pro‐inflammatory signalling molecules compared with the vehicle group, and reduced interstitial macrophage accrual. These data suggest that P2rx7 contributes to renal inflammation in diabetics and P2X7R antagonists may have therapeutic potential.Support or Funding InformationRIM is a BHF Immediate Postdoctoral Basic Science Research Fellow (Award number FS/15/60/31510). JWRB received a MRC/Kidney Research UK Joint Clinical Training Fellowship (Award number G0901956). We would like to thank GSK for gifting the P2X7k expressing gene‐targeted mice. FWKT is supported by the Diamond Fund from Imperial College Healthcare Charity. Part of this work is supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London.