A_2A adenosine receptor (A_2AAR) as a therapeutic target in diabetic retinopathy

In diabetic retinopathy (DR), abnormalities in vascular and neuronal function are closely related to the local production of inflammatory mediators whose potential source is microglia. A_2A adenosine receptor (A _2AAR) has been shown to possess anti-inflammatory properties that have not been studied in DR. Here, we evaluate the role of A_2AAR and its underlying signaling in retinal complications associated with diabetes. Initial studies in wild-type mice revealed that the treatment with the A _2AAR agonist resulted in marked decreases in hyperglycemia-induced retinal cell death and tumor necrosis factor (TNF)-α release. To further assess the role of A_2AAR in DR, we studied the effects of A _2AAR ablation on diabetes-induced retinal abnormalities. Diabetic A_2AAR^-/- mice had significantly more terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells, TNF-α release, and intercellular adhesion molecule-1 expression compared with diabetic wild-type mice. To explore a potential mechanism by which A _2AAR signaling regulates inflammation in DR, we performed additional studies using microglial cells treated with Amadori-glycated albumin, a risk factor in diabetic disorders. The results showed that activation of A _2AAR attenuated Amadori-glycated albumin-induced TNF-α release in a cAMP/exchange protein directly activated by cAMP-dependent mechanism and significantly repressed the inflammatory cascade, C-Raf/extracellular signal-regulated kinase (ERK), in activated microglia. Collectively, this work provides pharmacological and genetic evidence for A_2AAR signaling as a control point of cell death in DR and suggests that the retinal protective effect of A_2AAR is mediated by abrogating the inflammatory response that occurs in microglia via interaction with C-Raf/ ERK pathway.