Fenofibrate Ameliorates Oxidative Stress-Induced Retinal Microvascular Dysfunction in Diabetic Rats

Abstract

PURPOSE: The aim of this study is to investigate the effects of fenofibrate (FA) on microvascular dysfunction in the retina of diabetic rats, and to determine the underlying mechanism. METHODS: Streptozotocin (STZ)-induced diabetic rats and control rats were used in this study. A subgroup of STZ-induced diabetic rats was treated orally with vehicle or FA (100 mg/kg/day) for 24 weeks along with regular monitoring of body weight and serum parameters. At the end of the 24-week treatment, retinal vascular permeability was quantified by confocal microscopy using Evans blue as a tracer. Retinal capillary basement membrane thickness (BMT) was examined by transmission electron microscopy. The retinal reactive oxygen species (ROS) level was quantified by flow cytometry using a fluorescent probe. Levels of vascular endothelial growth factor (VEGF), nuclear facto (NF)-κB (p65), and thioredoxin interacting protein (TXNIP) were measured by Western blotting or enzyme-linked immunosorbent assay and real-time reverse transcription polymerase chain reaction. RESULTS: Retinal vascular permeability and BMT were significantly increased in diabetic rats compared to in non-diabetic control rats. Diabetes also increased the retinal ROS levels. These effects were associated with increased levels of VEGF, phosphorylation of p65(P-p65), and TXNIP. FA significantly ameliorated the retinal vascular permeability, alleviated retinal BMT, and reduced retinal ROS level. Consistent with these effects, FA also decreased VEGF and P-p65 expression and, at the same time, decreased TXNIP expression. CONCLUSIONS: FA prevents the retinal microvascular dysfunction induced by diabetes, likely by restoring VEGF and P-p65 levels, and possibly by reducing oxidative stress and TXNIP expression.