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Jing Zhang, Shihe Yang, Dongxu Fu, Mingyuan Wu, Mei Du, Kenneth Wilson, Timothy Lyons; Effects Of Fenofibrate On Modified-ldl-induced Retinal Cell Injury And Retinopathy In Stz-diabetic Mice. Invest. Ophthalmol. Vis. Sci. 2012;53(14):3283.
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© ARVO (1962-2015); The Authors (2016-present)
Fenofibrate, a peroxisome proliferator-activated receptor PPAR-a agonist, is used to treat hypertriglyceridemia. Recently, two large clinical studies independently demonstrated beneficial effects of fenofibrate in diabetic retinopathy (DR), but the mechanisms for such an effect are unknown. The aim of this study is to evaluate the mechanisms of fenofibrate action in DR using a novel animal model: modified LDL-enhanced DR in STZ-diabetic mice.
In vitro: Human Retinal Pigment Epithelium (RPE) cells were exposed to Native (N-) LDL or "highly oxidized glycated" (HOG-) LDL (200 mg/L) for 24 h with/without pre-treatment with fenofibrate (10, 50, 100 µM; 1h). RPE cell survival was determined by cell viability (CCK-8) assay. In vivo: STZ-induced diabetic and non-diabetic male C57BL/6J mice were fed different doses of fenofibrate (0, 100, 300mg/kg.d) for two months; then, to enhance DR, received intra-vitreal injection of N-LDL or HOG-LDL (5 µg/µl, 1µl/eye) or PBS (as control). Seven days later, electroretinograms (ERG), H&E, flat mount, retinal vascular permeability assay were performed; expression of inflammation (VEGF, GFAP), apoptosis (BAX) and ER stress (KDEL) markers were conducted by western blot analysis.
In vitro: Viability data for RPE cells were as follows (control (SFM) = 100%); HOG-LDL only: 60.9±6.5%; HOG-LDL pretreated with 10, 50, 100 µM fenofibrate: 65.7±3.9%, 75.9±2.5%*, 84.4±2.7%** respectively (mean±SE, * p<0.05, ** p<0.001 vs. HOG-LDL only, n=3). In vivo: In non-diabetic mice, neither intra-vitreal injection of HOG-LDL nor fenofibrate diets altered retinal function, structure (ERG and H&E staining), or vascular integrity, and no significant changes were noted in markers of inflammation, apoptosis or ER stress. In contrast, in diabetic mice, seven days after intra-vitreal injection, HOG-LDL disrupted retinal histology, impaired retinal function, and increased blood-retinal barrier breakdown. High but not low dose dietary fenofibrate improved retinal function and structure; significantly attenuated retinal vascular leakage and inflammation, and blocked the activation of apoptosis and ER stress.
Fenofibrate had beneficial effects on retinopathy in this STZ-diabetic mouse model. It countered the effects of intra-vitreal administration of LDL, suggesting that its protective effects operate directly within the retina.
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