Protective and Antioxidant Effects of PPARα in the Ischemic Retina

PURPOSE. Previous studies have demonstrated that peroxisome proliferator-activated receptor-alpha (PPAR alpha) agonists have therapeutic effects in diabetic retinopathy, although the mechanism of action remains incompletely understood. The purpose of this study was to evaluate PPAR alpha's protective effects in the ischemic retina, and to delineate its molecular mechanism of action. METHODS. For the oxygen-induced retinopathy (OIR) model, wild-type (WT), and PPARa knockout (PPAR alpha(-/-)) mice were exposed to 75% O-2 from postnatal day 7 (P7) to P12 and treated with the PPAR alpha agonist fenofibric acid (Feno-FA) from P12 to P16. At P17, the effects of Feno-FA on retinal glial fibrillary acidic protein (GFAP) expression, apoptotic DNA cleavage, and TUNEL labeling were analyzed. Cultured retinal cells were exposed to CoCl2 to induce hypoxia, and TUNEL staining and 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein dye were used to measure apoptosis and reactive oxygen species (ROS) generation. Western blotting was used to measure GFAP levels and cell signaling. RESULTS. Feno-FA decreased retinal apoptosis and oxidative stress in WT but not PPAR alpha(-/-) OIR mice. Peroxisome proliferator-activated receptor-alpha knockout OIR mice showed increased retinal cell death and glial activation in comparison to WT OIR mice. Feno-FA treatment and PPAR alpha overexpression protected cultured retinal cells from hypoxic cell death and decreased ROS levels. Nuclear hypoxia-inducible factor-alpha (HIF-1 alpha) and nicotine adenine dinucleotide phosphate oxidase-4 (Nox 4) were increased in OIR retinas and downregulated by Feno-FA in WT but not in PPAR alpha(-/-) mice. CONCLUSIONS. Peroxisome proliferator-activated receptor-alpha has a potent antiapoptotic effect in the ischemic retina. This protective effect may be mediated in part through downregulation of HIF-1 alpha/Nox 4 and consequently alleviation of oxidative stress.