Prostaglandin E2/EP2 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.

Opposing effects of IL-1β/COX-2/PGE2 pathway loop on islets in type 2 diabetes mellitus

“…It is well known that COX-2 plays a key role in PGE2 biosynthesis, which is related to proinflammatory reactions [12][13][14]. To determine the function of COX-2 in β cells, we first examined the effect of PGE2, the classical product of COX-2, on the β cell function.…”

Dysregulation of the NLRP3 Inflammasome in Diabetic Retinopathy and Potential Therapeutic Targets

“…70,73 Prostaglandin E2 Prostaglandin E2 (PGE2) is a proinflammatory molecule that has been noted to be statistically elevated by up to 53% in the vitreous of DR patients. 72,74,75 Likewise, its parent enzyme cyclooxygenase 2 (COX2) and its target receptor EP2R follow suit. 75,76 PGE2 is of importance because its inhibition has demonstrated an ability to suppress the progression of DR. 72 This is partly due to its possible role as an upstream NLRP3 activator.…”

“…72,74,75 Likewise, its parent enzyme cyclooxygenase 2 (COX2) and its target receptor EP2R follow suit. 75,76 PGE2 is of importance because its inhibition has demonstrated an ability to suppress the progression of DR. 72 This is partly due to its possible role as an upstream NLRP3 activator. 75 Additionally, in the diabetic retina, PGE2 exhibits a positive correlation with VEGF and promotes leukocyte adhesion, neovascularization, impairment of retinal vessels, retinal edema, and apoptosis.…”

“…75,76 PGE2 is of importance because its inhibition has demonstrated an ability to suppress the progression of DR. 72 This is partly due to its possible role as an upstream NLRP3 activator. 75 Additionally, in the diabetic retina, PGE2 exhibits a positive correlation with VEGF and promotes leukocyte adhesion, neovascularization, impairment of retinal vessels, retinal edema, and apoptosis. 72,74,75,77,78 Upon application of PGE2 receptor antagonists, the effects of PGE2 are diminished possibly due to an inhibited association of the NLRP3 with ASC oligomers.…”

“…75 Additionally, in the diabetic retina, PGE2 exhibits a positive correlation with VEGF and promotes leukocyte adhesion, neovascularization, impairment of retinal vessels, retinal edema, and apoptosis. 72,74,75,77,78 Upon application of PGE2 receptor antagonists, the effects of PGE2 are diminished possibly due to an inhibited association of the NLRP3 with ASC oligomers. 75 According to Wang et al, an understanding of how HG results in NLRP3 activation as mediated by PGE2 stems from its interaction with the EP2R.…”