Prostaglandin E 2 /EP 2 receptor signalling pathway promotes diabetic retinopathy in a rat model of diabetes

Abstract

Aims/hypothesis: Diabetic retinopathy is a common microvascular complication of diabetes mellitus and is initiated by inflammation and apoptosis-associated retinal endothelial cell damage. Prostaglandin E 2 (PGE 2 ) has emerged as a critical regulator of these biological processes. We hypothesised that modulating PGE 2 and its E-prostanoid receptor (EP 2 R) would prevent diabetes mellitus-induced inflammation and microvascular dysfunction. Methods: In a streptozotocin (STZ)-induced rat model of diabetes, rats received intravitreal injection of PGE 2 , butaprost (a PGE 2 /EP 2 R agonist) or AH6809 (an EP 2 R antagonist). Retinal histology, optical coherence tomography, ultrastructure of the retinal vascular and biochemical markers were assessed. Results: Intravitreal injection of PGE 2 and butaprost significantly accelerated retinal vascular leakage, leucostasis and endothelial cell apoptosis in STZ-induced diabetic rats. This response was ameliorated in diabetic rats pre-treated with AH6809. In addition, pre-treatment of human retinal microvascular endothelial cells with AH6809 attenuated PGE 2 - and butaprost-induced activation of caspase 1, activation of the complex containing nucleotide-binding domain and leucine rich repeat containing family, pyrin domain containing 3 (NLRP3) and apoptosis-associated speck-like protein containing a C-terminal caspase-activation and recruitment domain (ASC), and activation of the EP 2 R-coupled cAMP/protein kinase A/cAMP response element-binding protein signalling pathway. Conclusions/interpretation: The PGE 2 /EP 2 R signalling pathway is involved in STZ-induced diabetic retinopathy and could be considered as a potential target for diabetic retinopathy prevention and treatment.