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Nehal El-Sherbiny, Mohammad Naime, Saif Ahmad, Ahmed Elsherbini, Sadanand Fulzele, Mohammed Al-Gayyar, Laila A Eissa, Mamdouh El-Shishtawy, Gregory Liou; Inhibition of Adenosine Kinase Attenuates Inflammation in Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1155.
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© ARVO (1962-2015); The Authors (2016-present)
In diabetic retinopathy (DR), retinal inflammation is modulated by extracellular adenosine via A2A adenosine receptor (A2AAR). During retinal inflammation, ATP released from stressed cells is converted to adenosine by cell surface enzymes including ecto-5’-nucleotidase (CD73). Adenosine re-uptake by the equilibrative nucleoside transporter (ENT) allows AMP formation by adenosine kinase (AK). We aim to evaluate the role of CD73 and AK in regulating extracellular levels of adenosine in the retina. As AK is the key enzyme for the regulation of ambient levels of adenosine in the brain, we hypothesize a similar role for AK in the retina.
We tested the hypothesis by comparing retinal inflammation in wild type (WT) and CD73-/- (CD73KO) diabetic mice, and in diabetic mice treated and untreated with an AK inhibitor (AKI). We also compared TNF-α release in Amadori-glycated albumin (AGA)-treated retinal microglial cells ± AKI or CD73 inhibitor.
In WT diabetic mice, up-regulation of A2AAR, ENT1, Iba1, TNF-α, ICAM1, caspase3, and oxidative/nitrosative stress, and down-regulation of AK were revealed by Western blot, Real-Time PCR and immuno-staining analyses. However, CD73 expression remained unchanged. Treatment with an AKI reduced all these regulation differences. In contrast, no regulation differences between diabetic WT and CD73KO mice were observed. Moreover, treatment of AKI, but not CD73 inhibitor, blocked TNF-α release in AGA-treated microglial cells.
These results suggest a role for AK in regulating extracellular levels of adenosine in the retina. Inhibition of AK potentially amplifies the endogenous therapeutic effects of site- and event-specific accumulation of extracellular adenosine, which is of highly translational impact.
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