title: A(₂A) adenosine receptor (A(₂A)AR) as a therapeutic target in diabetic retinopathy.
abstract: 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.
authors.affiliation: Department of Ophthalmology, Medical College of Georgia, Augusta, Georgia, USA.
authors.forename: Ahmed S
authors.initials: AS
authors.lastname: Ibrahim
authors.forename: Mamdouh M
authors.initials: MM
authors.lastname: El-Shishtawy
authors.forename: Wenbo
authors.initials: W
authors.lastname: Zhang
authors.forename: Ruth B
authors.initials: RB
authors.lastname: Caldwell
authors.forename: Gregory I
authors.initials: GI
authors.lastname: Liou
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003930:Diabetic Retinopathy / Q000378:metabolism* / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D043683:Receptors, Adenosine A2 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D043683:Receptors, Adenosine A2; D014409:Tumor Necrosis Factor-alpha