title: Requirement of NOX2 expression in both retina and bone marrow for diabetes-induced retinal vascular injury.
abstract: OBJECTIVE
  Diabetic retinopathy, a major cause of blindness, is characterized by increased expression of vascular endothelial growth factor (VEGF), leukocyte attachment to the vessel walls and increased vascular permeability. Previous work has shown that reactive oxygen species (ROS) produced by the superoxide generating enzyme NOX2/NADPH oxidase play a crucial role in the vascular pathology. The aim of this work was to identify the cellular sources of the damaging NOX2 activity by studies using bone marrow chimera mice.
  
  
  METHODS
  Bone marrow cells were collected from the femurs and tibias of wild type and NOX2 deficient (NOX2(-/-)) donor mice and injected intravenously into lethally irradiated NOX2(-/-) and wild type recipients. Following recovery from radiation, mice were rendered diabetic by streptozotocin injections. The following groups of bone marrow chimeras were studied: non-diabetic WT → WT, diabetic WT → WT, diabetic WT → NOX2(-/-), diabetic NOX2(-/-) → WT. After 4 weeks of diabetes, early signs of retinopathy were examined by measuring ROS, expression of VEGF and ICAM-1, leukocyte attachment to the vessel wall and vascular permeability.
  
  
  RESULTS
  The retinas of the diabetic WT → WT chimeras showed significant increases in ROS as compared with the non-diabetic chimeras. These diabetes-induced alterations were correlated with increases in expression of VEGF and ICAM-1, leukocyte adhesion and vascular permeability. Each of these diabetes-induced alterations were significantly attenuated in the diabetic WT → NOX2(-/-) and NOX2(-/-) → WT chimera groups (p<0.05).
  
  
  CONCLUSIONS
  NOX2-generated ROS produced by both bone marrow-derived cells and resident retinal cells contribute importantly to retinal vascular injury in the diabetic retina. Targeting NOX2 in bone marrow and/or retinal cells may represent a novel therapeutic strategy for the treatment/prevention of vascular injury in the diabetic retina.
authors.affiliation: VA Medical Center, Augusta, Georgia, United States of America ; Vascular Biology Center, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Modesto
authors.initials: M
authors.lastname: Rojas
authors.affiliation: VA Medical Center, Augusta, Georgia, United States of America ; Vascular Biology Center, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Zhang
authors.affiliation: VA Medical Center, Augusta, Georgia, United States of America ; Vascular Biology Center, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Xu
authors.affiliation: VA Medical Center, Augusta, Georgia, United States of America ; Vascular Biology Center, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Tahira
authors.initials: T
authors.lastname: Lemtalsi
authors.affiliation: Immunotherapy Center, Georgia Reagents University, Augusta, Georgia, United States of America.
authors.forename: Phillip
authors.initials: P
authors.lastname: Chandler
authors.affiliation: Department of Pharmacology & Toxicology, Georgia Reagents University, Augusta, Georgia, United States of America.
authors.forename: Haroldo A
authors.initials: HA
authors.lastname: Toque
authors.affiliation: Department of Pharmacology & Toxicology, Georgia Reagents University, Augusta, Georgia, United States of America.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Caldwell
authors.affiliation: VA Medical Center, Augusta, Georgia, United States of America ; Vascular Biology Center, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Ruth B
authors.initials: RB
authors.lastname: Caldwell
mesh_terms: D000818:Animals; D001813:Blood-Retinal Barrier / Q000378:metabolism / Q000473:pathology; D001853:Bone Marrow / Q000378:metabolism*; D002448:Cell Adhesion; D002678:Chimera; D003921:Diabetes Mellitus, Experimental; D003930:Diabetic Retinopathy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D005838:Genotype; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics; D030421:Peroxynitrous Acid / Q000096:biosynthesis; D012160:Retina / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D008562:Membrane Glycoproteins; D042461:Vascular Endothelial Growth Factor A; D018799:Intercellular Adhesion Molecule-1; D030421:Peroxynitrous Acid; D014443:Tyrosine; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D017493:Leukocyte Common Antigens