title: Potential roles of adenosine deaminase-2 in diabetic retinopathy.
abstract: The early activation of microglia that induces retinal inflammation in DR may serve as a target for therapeutic intervention of DR. Our demonstration that retinal inflammation is attenuated via adenosine receptor A(2A)AR supports the hypothesis that a mechanism to maintain extracellular concentrations of adenosine important in normal physiology is impaired in DR. Extracellular concentrations of adenosine are regulated by the interplay of equiliberative nucleoside transporter (ENT)s with enzymes of adenosine metabolism including adenosine deaminase-1 (ADA1), adenosine kinase (AK) and CD73. In the vertebrates but not rodents, a macrophage-associated ADA2 is identified. The role of ADA2 is, therefore, understudied as the sequencing probes or antibodies to mouse ADA2 are not available. We identified increased ADA2 expression and activity in human and porcine retinas with diabetes, and in Amadori glycated albumin (AGA)- or hyperglycemia-treated porcine and human microglia. In rodent as well as porcine cells, modulation of TNF-α release is mediated by A(2A)AR. Quantitative analysis of normal and diabetic porcine retinas reveals that while the expression levels of ADA2, A2AAR, ENT1, TNF-α and MMP9 are increased, the levels of AK are reduced during inflammation as an endogenous protective mechanism. To determine the role of ADA2, we found that AGA induces ADA2 expression, ADA2 activity and TNF-α release, and that TNF-α release is blocked by ADA2-neutralizing antibody or ADA2 siRNA, but not by scrambled siRNA. These results suggest that retinal inflammation in DR is mediated by ADA2, and that the anti-inflammatory activity of A(2A)AR signaling is impaired in diabetes due to increased ADA2 activity.
authors.affiliation: Department of Ophthalmology, Georgia Regents University, Augusta, GA, United States.
authors.forename: Nehal M
authors.initials: NM
authors.lastname: Elsherbiny
authors.forename: Mohammad
authors.initials: M
authors.lastname: Naime
authors.forename: Saif
authors.initials: S
authors.lastname: Ahmad
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Elsherbini
authors.forename: Shuaib
authors.initials: S
authors.lastname: Mohammad
authors.forename: Sadanand
authors.initials: S
authors.lastname: Fulzele
authors.forename: Azza B
authors.initials: AB
authors.lastname: El-Remessy
authors.forename: Mohammed M
authors.initials: MM
authors.lastname: Al-Gayyar
authors.forename: Laila A
authors.initials: LA
authors.lastname: Eissa
authors.forename: Mamdouh M
authors.initials: MM
authors.lastname: El-Shishtawy
authors.forename: Guichun
authors.initials: G
authors.lastname: Han
authors.forename: Richard
authors.initials: R
authors.lastname: White
authors.forename: Toque Flores
authors.initials: TF
authors.lastname: Haroldo
authors.forename: Gregory I
authors.initials: GI
authors.lastname: Liou
mesh_terms: D015720:5'-Nucleotidase / Q000235:genetics / Q000378:metabolism; D000241:Adenosine / Q000378:metabolism; D000243:Adenosine Deaminase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015687:Cell Hypoxia; D003930:Diabetic Retinopathy / Q000201:enzymology / Q000473:pathology*; D004789:Enzyme Activation; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D017127:Glycation End Products, Advanced; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D017628:Microglia / Q000187:drug effects / Q000201:enzymology; D008875:Middle Aged; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D012160:Retina / Q000201:enzymology* / Q000473:pathology; D012709:Serum Albumin / Q000494:pharmacology; D015398:Signal Transduction; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D020298:U937 Cells; D000093423:Glycated Serum Albumin
chemical_list: D058851:GPI-Linked Proteins; D017127:Glycation End Products, Advanced; D036341:Intercellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D018047:Receptors, Purinergic P1; D012709:Serum Albumin; D014409:Tumor Necrosis Factor-alpha; D015720:5'-Nucleotidase; C548241:NT5E protein, human; C408373:ADA2 protein, human; D000243:Adenosine Deaminase; D000241:Adenosine; D000093423:Glycated Serum Albumin
keywords: ADA2; AGA; AK; Adenosine deaminase-2; Adenosine kinase inhibitor; Adenosine receptor signaling; CD73; Diabetic retinopathy; ENT1; adenosine deaminase-2; adenosine kinase; amadori glycated albumin; ecto-5′-nucleotidase; equilibrative nucleoside transporter 1