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Elizabeth P Moran, Lexi Ding, Rui Cheng, Zhongxiao Wang, Qian Chen, Yusuke Takahashi, Jian-Xing Ma; Neuroprotective and Antioxidant Effects of a PPAR-alpha Agonist in Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1052.
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© ARVO (1962-2015); The Authors (2016-present)
Clinical trials identified that the PPARα agonist fenofibrate had a therapeutic effect in diabetic retinopathy (DR), although its physiological and molecular mechanisms of action remain poorly understood. The purpose of this study was to determine whether PPARα activation has a neuroprotective effect in a type 1 diabetic DR animal model, and to delineate its molecular mechanism of action.
Diabetes was induced with streptozotocin (STZ) in male Sprague-Dawley rats. Three weeks after hyperglycemia was confirmed, diabetic and non-diabetic rats were treated with the bioactive fenofibrate metabolite fenofibric acid (FA) for one week prior to the experimental endpoint. Rats were euthanized and perfused with PBS. Retinas were enucleated and subjected to a cell death ELISA and Western blotting for GFAP and UCP2. R28 rod precursor cells were subjected to 4-HNE and treated with FA or infected with PPARα-expressing adenovirus (ad-PPARα), and trypan blue dye exclusion and H2-DCFDA were used to quantify cell viability and ROS production, respectively. R28 cells were also treated with FA or infected with ad-PPARα and subjected to UCP2 Western blotting.
Retinal neurodegeneration and glial activation were significantly increased in diabetic animals, and were restored nearly to baseline by FA. FA also up-regulated retinal UCP2 expression in the diabetic animals. Both FA and PPARα overexpression decreased ROS production and protected R28 cells against HNE-induced apoptosis, and up-regulated UCP2 in R28 cells.
Together, these data suggest that PPARα has a potent neuroprotective effect against diabetes-related oxidative stress, which may be responsible for fenofibrate’s therapeutic effect in DR. This protective effect may be mediated in part through upregulation of the mitochondrial uncoupling protein UCP2 and a subsequent decrease in mitochondrial ROS production.
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