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Ying-Jung Hsu, Sheng-Li Cho, Chang-Hao Yang; Protective effect of fenofibrate on oxidative stress induced retinal neuronal cell damage. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1797.
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Diabetic retinopathy represents the most common cause of blindness worldwide. Oxidative stress is associated with the development of diabetic retinopathy. Fenofibrate, a PPAR-α agonist, is used clinically to treat hypertriglyceridemia and hyperlipidemia. Two recent clinical studies (FIELD and ACCORD) showed that fenofibrate reduces the progression of diabetic retinopathy. Our hypothesis is that fenofibrate could counteract oxidative stress within diabetic eyes and attenuate oxidative stress-induced cell death, thereby preventing diabetic retinae from DR progression with subsequent loss of vision.
Paraquat (PQ), a redox active compound which induces oxidative stress via increasing free radical generation, was added to induce oxidative stress on RGC-5 cells. Cells were pre-treated by various concentrations of fenofibrate (FA) before PQ was added. We measured cell viability by MTT assay. Reactive oxygene species (ROS) production was measured by staining with DAPI and CellROX® oxidative stress reagents. We detected cellular apoptotic cells by flow cytometry with annexin V and PI labeling. Mitochondrial membrane potential was measured by JC-1 mitochondrial membrane potential assay kit. mRNA levels such as Bax, Bcl-2, Bcl-xL, heme oxygenase-1 (HO-1), peroxiredoxin 1 (Prx-1) and thioredoxin (TRX) were investigated by PCR. Proteins involved in apoptosis, including cytochrome c, p53, Bax and Bcl-2 were investigated by western blotting.
After 24 hours of oxidative stress, the RGC-5 survival rate decreased with the concentration of PQ. Fenofibrate pre-treatment decreased ROS production in RGC-5 cells under PQ stimulation. Fenofibrate decreased apoptosis under PQ-induced oxidative stress, and also reduced the proportion of RGC-5 cells with mitochondrial damage. Fenofibrate increased the mRNA level of HO-1 and BCL-2, whereas reduced the levels of TRX-1, TRX-2, Bcl-xL and Bax in PQ-stimulated RGC-5 cells. About apoptosis related signaling pathway, fenofibrate could repress the protein expression of cytochrome c, Bax, p53 and down-regulation in Bcl-2 protein.
These effects of fenofibrate may be, at least in part, attributable to its anti-oxidative ability. Fenofibrate is probably valuable for the therapy of ocular oxidative stress disorders, such as diabetic retinopathy.
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