Pharmacological blockade of the P2X7 receptor reverses retinal damage in a rat model of type 1 diabetes

  • Acta Diabetol. 2019 Sep;56(9):1031-1036. doi: 10.1007/s00592-019-01343-4.
Carmen Clapp  1 ,  Nundehui Diaz-Lezama  1 ,  Elva Adan-Castro  1 ,  Gabriela Ramirez-Hernandez  1 ,  Bibiana Moreno-Carranza  1 ,  Alba Clara Sarti  2 ,  Simonetta Falzoni  2 ,  Anna Solini  3 ,  Francesco Di Virgilio  4
Affiliations
  • 1. Institute of Neurobiology, National University of Mexico [UNAM], Querétaro, Mexico.
  • 2. Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Via Borsari 46, 44121, Ferrara, Italy.
  • 3. Department of Surgical, Medical, Molecular, and Critical Area Pathology, University of Pisa, Pisa, Italy.
  • 4. Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Via Borsari 46, 44121, Ferrara, Italy. [email protected].
PMID: 30982154 DOI: 10.1007/s00592-019-01343-4
Abstract

Aims: Retinopathy is a leading cause of vision impairment in diabetes. Its pathogenesis involves inflammation, pathological angiogenesis, neuronal and glial dysfunction. The purinergic P2X7 Receptor (P2X7R) has a leading role in inflammation and angiogenesis. Potent and selective P2X7R blockers have been synthesized and tested in Phase I/II clinical studies. We hypothesize that P2X7R blockade will ameliorate diabetes-related pathological retinal changes.

Methods: Streptozotocin (STZ)-treated rats were intraperitoneally inoculated with either of two small molecule P2X7R receptor inhibitors, A740003 and AZ10606120, and after blood glucose levels increased to above 400 mg/dL, retinae were analyzed for P2X7R expression, vascular permeability, VEGF, and IL-6 expression.

Results: STZ administration caused a near fourfold increase in blood glucose, a large increase in retinal microvasculature permeability, as well as in retinal P2X7R, VEGF, and IL-6 expression. P2X7R blockade fully reversed retinal vascular permeability increase, VEGF accumulation, and IL-6 expression, with no effect on blood glucose.

Conclusion: P2X7R blockade might be promising strategy for the treatment of microvascular changes observed in the early phases of diabetic retinopathy.

Keywords
Diabetic retinopathy; Extracellular ATP; Inflammation; P2X7; Retinal vasopermeability.
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