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A more recent version of this article appeared on February 1, 2009
 (Investigative Ophthalmology and Visual Science. )
© 2008 by The Association for Research in Vision and Ophthalmology, Inc.
doi:10.1167/iovs.08-2005
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Article

Suppression of Retinal Peroxisome Proliferator Activated Receptor-gamma in Experimental Diabetes and Oxygen-Induced Retinopathy: Role of NADPH Oxidase

Amany Tawfik 1*, Tammy Sanders 1, Khalid Kahook 1, Sara Akeel 2, Ahmed El-marakby 3, and Mohamed Al-Shabrawey 4

1 Oral Biology and Anatomy, School of Dentistry, Medical College of Georgia, Augusta, Georgia, United States
2 Oral Biology and anatomy, Medical College of Georgia, Augusta, Georgia, United States
3 Vascular Biology Center, Medical college of Georgia, Augusta, Georgia, United States
4 Oral Biology and Anatomy, Medical College of Georgia, Augusta, Georgia, United States; Opthalmology, Medical College of Georgia, Augusta, Georgia, United States

* To whom correspondence should be addressed. E-mail: atawfik{at}mcg.edu.


  Abstract

Purpose: Recently we 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 experimental model of diabetes. So, 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 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 diphenleneiodonium, DPI). Western blotting and Immunofluorescence were used to evaluate PPAR {gamma}expression. Activation of NF{kappa}B was measured using transcription factor assay kit and Western blotting analysis of phospho-NF{kappa}B. PPAR{gamma} expression was also tested in OIR and lipoploysaccharides-induced retinal inflammation. Results: Retinal expression of PPAR{gamma} was suppressed in experimental models of diabetes, OIR and retinal inflammation. This was associated with activation of NF{kappa}B in 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. Conclusion: Suppression of PPAR{gamma} is involved in the pathogenesis of diabetic retinopathy and OIR. NADPH oxidase could be an upstream mediator of these changes.

Key Words: diabetic retinopathy, oxidative damage, retinopathy of prematurity, anti-inflammatory agents






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