Abstract
Purpose: :
Our goal is to develop an early therapeutic intervention against inflammation in diabetic retinopathy (DR) before its progression is irreversible. We have shown that Amadori-glycated albumin (AGA), a well-documented risk factor in diabetes, induces microglia-mediated retinal endothelial inflammation, suggesting that microglial activation causes DR, and may serve as a target for therapeutic intervention. We have also shown that retinal inflammation in diabetes is modulated by extracellular adenosine via adenosine receptor A2AAR-cAMP signaling, that A2AAR KO mice with diabetes have a detrimental phenotype, and that A2AAR agonist protects against retinal inflammation. These results support our central hypothesis: that adenosine is important in diabetes, and that abnormal adenosine metabolism contributes to DR. Extracellular concentrations of adenosine are regulated by interplay of nucleoside transporters with intracellular and extracellular enzymes of adenosine metabolism. Released ATP is converted by 5’-ectonucleotidase (CD73) to adenosine, which is catabolized to inosine by the ubiquitous adenosine deaminase1 (ADA1) and the monocyte-macrophage-specific ADA2, an enzyme that is identified in all vertebrates except rodents.
Methods: :
We used a porcine model of DR, which shares a similar immune system with human, to study the mechanism that regulates the synthesis and degradation of extracellular adenosine.
Results: :
Role of adenosine is understudied as ADA2 has not been identified in mice. However, our preliminary data in human and porcine retinas have revealed some clue about adenosine’s role in diabetes. In human and porcine retinas with diabetes, there was an increased expression or activity of ADA2, but not ADA1 or CD73. Treatment of porcine retinal microglial cells with AGA resulted in enhanced ADA2 activity and TNF-α release, and these effects were reversed by A2AAR agonist or ADA2-neutralizing antibody.
Conclusions: :
These results suggest that increased ADA2 activity causes retinal inflammation in diabetes, and that ADA2 activity is up-regulated via an inflammatory pathway.
Keywords: adenosine • microglia • diabetic retinopathy