Abstract
PURPOSE. Recently, the authors have shown that NADPH oxidase is positively correlated with increased leukocyte adhesion and vascular leakage in diabetes and neovascularization in oxygen-induced retinopathy (OIR). Peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists have been shown to prevent vascular inflammation and leakage in an experimental model of diabetes. The goal of this study was to investigate whether there is a link between NADPH oxidase and PPAR gamma that leads to vascular dysfunction in diabetic retina or OIR.
METHODS. Diabetes was induced with streptozotocin in wildtype mice or NOX2 knockout mice. One group of wild-type mice was treated with apocynin. Bovine retinal endothelial cells (BRECs) were treated with normal glucose (5 mM) or high glucose (25 mM) in the presence or absence of superoxide dismutase ( SOD) or NADPH oxidase inhibitors (apocynin or diphenyleneiodonium [DPI]). Western blotting and immunofluorescence were used to evaluate PPAR gamma expression. Activation of nuclear factor (NF)kappa B was measured using the transcription factor assay kit and Western blot analysis of phospho-NF kappa B. PPAR gamma expression was also tested in OIR and lipopolysaccharide-induced retinal inflammation.
RESULTS. Retinal expression of PPAR gamma was suppressed in experimental models of diabetes, OIR, and retinal inflammation. This was associated with the activation of NF kappa B in the diabetic retina. These effects were prevented by apocynin or deletion of NOX2. PPAR gamma expression was also suppressed in endothelial cells treated with high glucose, and this was prevented by apocynin, DPI, and SOD.
CONCLUSIONS. Suppression of PPAR gamma is involved in the pathogenesis of diabetic retinopathy and OIR. NADPH oxidase could be an upstream mediator of these changes. (Invest Ophthalmol Vis Sci. 2009; 50: 878-884) DOI: 10.1167/iovs.08-2005