Target size of the adenosine Ri receptor.
Ontology highlight
ABSTRACT:
SUBMITTER: Frame LT
PROVIDER: S-EPMC1146730 | biostudies-other | 1986 Apr
REPOSITORIES: biostudies-other
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Project description: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.
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