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N. Fatteh, A. Ibrahim, G. Liou; The Role of Adenosine in the Diabetic Retina. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5085.
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Recent evidence has indicated that adenosine can regulate retinal immune cell function and barrier function of retinal vasculature. Therefore, understanding the mechanism of this regulation may provide a use for targeted intervention in diabetic retinopathy. Ischemic stress in the diabetic retina is known to activate microglia, cause neuronal cell death, and breakdown of the blood-retinal barrier. Ischemic stress also causes the release of adenosine through the bi-directional equilibrative nucleoside transporters (ENT). Extracellular adenosine is known to attenuate inflammation by activating A2a receptor, and A2a receptor-selective agonists have been shown to be effective in anti-inflammation in acute or chronic inflammatory diseases. In high glucose-treated cardiac fibroblasts, however, decreased adenosine release and uptake were measured in comparison to low glucose-treated cells. This suggests impairment in the function of ENT and the subsequent adenosine-A2a receptor signaling in diabetes. This study is the first step to test the hypothesis that the anti-inflammatory function of adenosine-A2a receptor signaling is impaired in the diabetic retina.
Primary cultures of rat retinal microglial cells were treated with or without Amadori-glycated albumin (AGA), which has been implicated as a causal factor in diabetic complications. TNF-α levels in the media were measured by ELISA. Adenosine uptake by microglial cells was determined within one minute after the addition of [2-3H] adenosine. Washed cells were solubilized and radioactivity quantified. For adenosine release, cellular ATP was labeled with [8-14C] adenine, and ATP was depleted in the presence of 2-deoxyglucose and antimycin A. At appropriate time points within 15 minutes of ATP depletion, medium aliquots containing released adenosine was separated on silica gel plate and quantified.
Retinal microglial cells showed a significant increase in TNF-α release after AGA treatment. Adenosine uptake and release by these cells were inhibited by AGA treatment.
These results suggest that cell protection mechanisms effected by adenosine are impaired in the diabetic retina. Activation of A2a receptor by a selective agonist, as shown in other organ systems, may be effective in anti-inflammation in the diabetic retina.
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