Abstract
The early stages of diabetic retinopathy (DR) are characterized by alterations similar to neurodegenerative and inflammatory conditions such as increased neural apoptosis, microglial cell activation and amplified production of pro-inflammatory cytokines. Adenosine regulates several physiological functions by stimulating four subtypes of receptors, A1AR, A2AAR, A2BAR, and A3AR. Although the adenosinergic signaling system is affected by diabetes in several tissues, it is unknown whether diabetic conditions in the retina can also affect it. Adenosine delivers potent suppressive effects on virtually all cells of the immune system, but its potential role in the context of DR has yet to be studied in full. In this study, we used primary mixed cultures of rat retinal cells exposed to high glucose conditions, to mimic hyperglycemia, and a streptozotocin rat model of type 1 diabetes to determine the effect diabetes/hyperglycemia have on the expression and protein levels of adenosine receptors and of the enzymes adenosine deaminase and adenosine kinase. We found elevated mRNA and protein levels of A1AR and A2AAR, in retinal cell cultures under high glucose conditions and a transient increase in the levels of the same receptors in diabetic retinas. Adenosine deaminase and adenosine kinase expression and protein levels showed a significant decrease in diabetic retinas 30 days after diabetes induction. An enzymatic assay performed in retinal cell cultures revealed a marked decrease in the activity of adenosine deaminase under high glucose conditions. We also found an increase in extracellular adenosine levels accompanied by a decrease in intracellular levels when retinal cells were subjected to high glucose conditions. In conclusion, this study shows that several components of the retinal adenosinergic system are affected by diabetes and high glucose conditions, and the modulation observed may uncover a possible mechanism for the alleviation of the inflammatory and excitotoxic conditions observed in diabetic retinas.
Highlights
Diabetic retinopathy (DR) is one of the major and most serious complication of both type 1 and type 2 diabetes
Similar to what was observed for the receptors protein levels, the alterations occurring to A1AR and A2AAR expression levels were not due to changes in osmolarity since cells incubated with mannitol did not present expression levels different from those observed in cells cultured in control conditions
The present study provides the first clear evidence that the retinal adenosinergic system is affected by diabetes
Summary
Diabetic retinopathy (DR) is one of the major and most serious complication of both type 1 and type 2 diabetes. After 20 years of diabetes, most patients with type 1 and more than 60% of patients with type 2 diabetes have some degree of retinopathy, the most frequent cause of new cases of blindness among adults aged 20–74 years. A purine nucleoside, regulates a variety of physiological functions by stimulating specific extracellular receptors. Under adverse conditions such as inflammation, adenosine production by damaged neurons is increased and helps to protect tissue against excessive damage [8]. Previous studies have reported compelling evidence that diabetes can modulate the density and activity of several components of the adenosinergic signaling system in different tissues [11,12,13]. Before tackling the potential for protection, it is first necessary to investigate if diabetic, or hyperglycemia can trigger modifications in the adenosinergic system with potential pathophysiological implications for DR
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