June 2013
Volume 54, Issue 15
Free
ARVO Annual Meeting Abstract  |   June 2013
Inhibition of Adenosine Kinase Attenuates Inflammation in Diabetic Retinopathy
Author Affiliations & Notes
  • Nehal El-Sherbiny
    Opthalmology, Georgia Health Sciences University, Augusta, GA
    Clinical Biochemistry, Mansoura University, Mansoura, Egypt
  • Mohammad Naime
    Opthalmology, Georgia Health Sciences University, Augusta, GA
  • Saif Ahmad
    Opthalmology, Georgia Health Sciences University, Augusta, GA
  • Ahmed Elsherbini
    Opthalmology, Georgia Health Sciences University, Augusta, GA
  • Sadanand Fulzele
    Orthopedics, Georgia Health Sciences University, Augusta, GA
  • Mohammed Al-Gayyar
    Clinical Biochemistry, Mansoura University, Mansoura, Egypt
  • Laila A Eissa
    Clinical Biochemistry, Mansoura University, Mansoura, Egypt
  • Mamdouh El-Shishtawy
    Clinical Biochemistry, Mansoura University, Mansoura, Egypt
  • Gregory Liou
    Opthalmology, Georgia Health Sciences University, Augusta, GA
  • Footnotes
    Commercial Relationships Nehal El-Sherbiny, None; Mohammad Naime, None; Saif Ahmad, None; Ahmed Elsherbini, None; Sadanand Fulzele, None; Mohammed Al-Gayyar, None; Laila A Eissa, None; Mamdouh El-Shishtawy, None; Gregory Liou, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2013, Vol.54, 1155. doi:
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    • Get Citation

      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)

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Abstract
 
Purpose
 

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.

 
Methods
 

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.

 
Results
 

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.

 
Conclusions
 

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.

 
 
The hypothetical mechanism of adenosine anti-inflammation signaling impairment in diabetic retinopathy (DR). Hyperglycemic stress causes adenosine release as well as release of pro-inflammatory cytokines, leading to DR. Adenosine-initiated anti-inflammation via A2AAR-cAMP signaling is impaired in DR due to an imbalance in adenosine formation and metabolism in the retina.
 
The hypothetical mechanism of adenosine anti-inflammation signaling impairment in diabetic retinopathy (DR). Hyperglycemic stress causes adenosine release as well as release of pro-inflammatory cytokines, leading to DR. Adenosine-initiated anti-inflammation via A2AAR-cAMP signaling is impaired in DR due to an imbalance in adenosine formation and metabolism in the retina.
 
Keywords: 499 diabetic retinopathy • 557 inflammation • 410 adenosine  
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