Protective and antioxidant effects of PPARα in the ischemic retina.

Abstract

PURPOSE:

Previous studies have demonstrated that peroxisome proliferator-activated receptor-alpha (PPARα) agonists have therapeutic effects in diabetic retinopathy, although the mechanism of action remains incompletely understood. The purpose of this study was to evaluate PPARα'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 PPARα knockout (PPARα(-/-)) mice were exposed to 75% O₂ from postnatal day 7 (P7) to P12 and treated with the PPARα 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 PPARα(-/-) 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 PPARα overexpression protected cultured retinal cells from hypoxic cell death and decreased ROS levels. Nuclear hypoxia-inducible factor-α (HIF-1α) and nicotine adenine dinucleotide phosphate oxidase-4 (Nox 4) were increased in OIR retinas and downregulated by Feno-FA in WT but not in PPARα(-/-) 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-1α/Nox 4 and consequently alleviation of oxidative stress.

• Authors: Elizabeth Moran, Lexi Ding, Zhongxiao Wang, Rui Cheng, Qian Chen, Robert Moore, Yusuke Takahashi, Jian-xing Ma
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 55 Issue 7 Pg. 4568-76 (May 13 2014) ISSN: 1552-5783 [Electronic] United States
• PMID: 24825105 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

Chemical References

• Antioxidants
• Glial Fibrillary Acidic Protein
• Hif1a protein, mouse
• Hypolipidemic Agents
• Hypoxia-Inducible Factor 1, alpha Subunit
• Nerve Tissue Proteins
• PPAR alpha
• Reactive Oxygen Species
• glial fibrillary astrocytic protein, mouse
• fenofibric acid
• NADPH Oxidase 4
• NADPH Oxidases
• Nox4 protein, mouse
• Oxygen
• Fenofibrate

Topics

• Animals
• Animals, Newborn
• Antioxidants (physiology)
• Apoptosis (drug effects)
• Blotting, Western
• Cells, Cultured
• Disease Models, Animal
• Enzyme-Linked Immunosorbent Assay
• Fenofibrate (analogs & derivatives, therapeutic use)
• Glial Fibrillary Acidic Protein
• Hypolipidemic Agents (therapeutic use)
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• In Situ Nick-End Labeling
• Ischemia (metabolism, pathology, prevention & control)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• NADPH Oxidase 4
• NADPH Oxidases (metabolism)
• Nerve Tissue Proteins (metabolism)
• Oxidative Stress (drug effects)
• Oxygen (toxicity)
• PPAR alpha (agonists, physiology)
• Reactive Oxygen Species (metabolism)
• Retinal Diseases (metabolism, pathology, prevention & control)
• Retinal Vessels (physiopathology)