A(₂A) adenosine receptor (A(₂A)AR) 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(₂A)AR) has been shown to possess anti-inflammatory properties that have not been studied in DR. Here, we evaluate the role of A(₂A)AR and its underlying signaling in retinal complications associated with diabetes. Initial studies in wild-type mice revealed that the treatment with the A(₂A)AR 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(₂A)AR in DR, we studied the effects of A(₂A)AR ablation on diabetes-induced retinal abnormalities. Diabetic A(₂A)AR(-/-) 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(₂A)AR 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(₂A)AR 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(₂A)AR signaling as a control point of cell death in DR and suggests that the retinal protective effect of A(2A)AR is mediated by abrogating the inflammatory response that occurs in microglia via interaction with C-Raf/ERK pathway.