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Veluchamy A Barathi, Yeo Sia Wey, Chi D Luu, Tien Y Wong, Shyam S Chaurasia, Ecosse L Lamoureux; Effect of Fenofibrate in Hyperglycemic Mice Retina: Role of downstream Inflammatory Cytokines in Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1058.
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Inflammation plays a substantial role in the development of diabetic retinopathy (DR). Fenofibrate, a lipid reducing drug is known to decrease inflammation and improve insulin sensitivity, and reduce the risk of DR. We aim to determine the effectiveness of fenofibrate in the treatment of diabetes by detecting the levels of downstream inflammatory mediators (IM) in hyperglycemic mice retina.
Wild type mice were fed with high fat diet (HFD), HFD with fenofibrate (30mg/kg) and normal diet for 10 weeks. Akita (Ins2Akita) mice received a dose of 50mg/kg fenofibrate and saline weekly via oral medication for 10 weeks (n=20 mice per group). Pre and post-treatment blood glucose level (BGL) measurements and retinal assessments were conducted weekly. To determine the effectiveness of fenofibrate, 11 IM levels, namely atrial natriuretic peptide (ANP), Fractalkine (CX3CR1), ICAM-1, interleukin-1 beta (IL-1β), interleukin-6 (IL-6), MCP-1, NADPH oxidase 2 (NOX2), NADPH oxidase 4 (NOX4), reactive oxygen species (ROS-1), tumor necrosis factor alpha (TNF-α) and vascular endothelial factor A (VEGFa), were monitored both pre and post treatment. Quantitative Real-Time-PCR was done to quantify the expression levels of the IMs. This was further validated by Western bot and immunohistochemistry analysis.
Hyperglycemic mice body weight increased by 68% after 10 weeks compared to 22% in the fenofibrate group (p = 0.00004). Hyperglycemic group BGL increased fourfold by 408% at 10 weeks and no change in the fenofibrate group, 103% ((p = 0.00003). Fenofibrate treated mice exhibited retinal functional changes almost similar to those of the control group. Some vascular pathology characteristics such as slight leakages observed in Akita pre-treament were improved upon fenofibrate treatment. Hyperglycemic mice were seen to exhibit high levels of pro-angiogenic, oxidative stress inducers and other inflammation associated cytokines and low levels of anti-angiogenic ANP. Down-regulation of IM expressions was observed in the fenofibrate treated group.
Fenofibrate generally lowered the expression levels of IMs in treated hyperglycemic mice, particularly for the four most important IMs: ICAM-1, MCP-1, TNF-α, VEGFa. These findings validate the effectiveness of fenofibrate in diabetes-related complications.
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