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Amany Tawfik, Tammy Sanders, Khalid Kahook, Sara Akeel, Ahmed Elmarakby, Mohamed Al-Shabrawey; Suppression of Retinal Peroxisome Proliferator-Activated Receptor γ in Experimental Diabetes and Oxygen-Induced Retinopathy: Role of NADPH Oxidase. Invest. Ophthalmol. Vis. Sci. 2009;50(2):878-884. doi: 10.1167/iovs.08-2005.
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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 (PPARγ) 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 PPARγ that leads to vascular dysfunction in diabetic retina or OIR.
methods. Diabetes was induced with streptozotocin in wild-type 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 PPARγ expression. Activation of nuclear factor (NF)κB was measured using the transcription factor assay kit and Western blot analysis of phospho-NFκB. PPARγ expression was also tested in OIR and lipopolysaccharide-induced retinal inflammation.
results. Retinal expression of PPARγ was suppressed in experimental models of diabetes, OIR, and retinal inflammation. This was associated with the activation of NFκB in the diabetic retina. These effects were prevented by apocynin or deletion of NOX2. PPARγ expression was also suppressed in endothelial cells treated with high glucose, and this was prevented by apocynin, DPI, and SOD.
conclusions. Suppression of PPARγ is involved in the pathogenesis of diabetic retinopathy and OIR. NADPH oxidase could be an upstream mediator of these changes.
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