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Modesto A. Rojas, Wenbo Zhang, Zhimin Xu, Phillip Chandler, Robert W. Caldwell, Ruth B. Caldwell; Mechanisms of Diabetic Retinopathy: Role of NOX2 in Retinal and Bone Marrow-derived Cells. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2419.
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© ARVO (1962-2015); The Authors (2016-present)
Diabetic retinopathy, the most common cause of blindness in US adults of working age, is characterized by increased expression of VEGF, vascular inflammation and increased permeability. Our previous studies have shown that reactive oxygen species (ROS) produced by the superoxide generating enzyme NOX2 NADPH oxidase play a crucial role in the vascular injury associated with diabetic retinopathy. We have now investigated the specific cellular source(s) of the damaging NOX2 activity by studies using bone marrow chimeric mice.
Bone marrow cells were collected from the femurs and tibias of healthy wild type and NOX2-/- donor mice and a 200µl cell suspension (1 x 107 nucleated cells) was injected intravenously into previously irradiated NOX2-/- and wild type recipients. Three weeks after bone marrow transplantation diabetes was induced by streptozotocin treatment. 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, retinopathy was assessed by measuring formation of superoxide and nitric oxide (NO), expression of VEGF and ICAM-1, leukocyte attachment to the vessel wall and vascular permeability.
The retinas of the diabetic WT→WT chimeras showed significant increases in superoxide formation and decreases in NO formation 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 was significantly attenuated in the diabetic WT→NOX2-/- and NOX2-/- →WT chimeras (p<0.05).
These results indicate that NOX2-generated ROS produced by both BM-derived cells and resident retinal cells contribute importantly to retinal vascular injury in diabetic retinopathy.Targeting NOX2 in either bone marrow or retinal cells represents a novel therapeutic strategy for the treatment/ prevention of diabetic retinopathy.
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