A2A adenosine receptor (A2AAR) as a therapeutic target in diabetic retinopathy

Ahmed S. Ibrahim, Mamdouh M. El-shishtawy, Wenbo Zhang, Ruth B. Caldwell, Gregory I. Liou

Research output: Contribution to journalArticle

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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. A2A 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 A2AAR 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 A2AAR in DR, we studied the effects of A 2AAR ablation on diabetes-induced retinal abnormalities. Diabetic A2AAR-/- 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 A2AAR signaling as a control point of cell death in DR and suggests that the retinal protective effect of A2AAR is mediated by abrogating the inflammatory response that occurs in microglia via interaction with C-Raf/ ERK pathway.

Original languageEnglish
Pages (from-to)2136-2145
Number of pages10
JournalAmerican Journal of Pathology
Volume178
Issue number5
DOIs
StatePublished - May 2011
Externally publishedYes

Fingerprint

Adenosine A2A Receptors
Diabetic Retinopathy
Microglia
Therapeutics
Tumor Necrosis Factor-alpha
Cell Death
Adenosine A2 Receptor Agonists
DNA Nucleotidylexotransferase
MAP Kinase Signaling System
Extracellular Signal-Regulated MAP Kinases
Intercellular Adhesion Molecule-1
Hyperglycemia
Blood Vessels
Anti-Inflammatory Agents
Pharmacology
Inflammation

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Medicine(all)

Cite this

A2A adenosine receptor (A2AAR) as a therapeutic target in diabetic retinopathy. / Ibrahim, Ahmed S.; El-shishtawy, Mamdouh M.; Zhang, Wenbo; Caldwell, Ruth B.; Liou, Gregory I.

In: American Journal of Pathology, Vol. 178, No. 5, 05.2011, p. 2136-2145.

Research output: Contribution to journalArticle

Ibrahim, Ahmed S. ; El-shishtawy, Mamdouh M. ; Zhang, Wenbo ; Caldwell, Ruth B. ; Liou, Gregory I. / A2A adenosine receptor (A2AAR) as a therapeutic target in diabetic retinopathy. In: American Journal of Pathology. 2011 ; Vol. 178, No. 5. pp. 2136-2145.
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