Therapeutic Effects of PPARα Agonists on Diabetic Retinopathy in Type 1 Diabetes Models
- Ying Chen1,2,
- Yang Hu1,2,
- Mingkai Lin1,2,3,
- Alicia J. Jenkins2,4,
- Anthony C. Keech5,
- Robert Mott1,
- Timothy J. Lyons2 and
- Jian-xing Ma1,2⇓
- 1Department of Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
- 2Harold Hamm Diabetes Center, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
- 3Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
- 4Department of Medicine, The University of Melbourne, Melbourne, Australia
- 5National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia
- Corresponding author: Jian-xing Ma, .
Y.C. and Y.H. contributed equally to this study.
Retinal vascular leakage, inflammation, and neovascularization (NV) are features of diabetic retinopathy (DR). Fenofibrate, a peroxisome proliferator–activated receptor α (PPARα) agonist, has shown robust protective effects against DR in type 2 diabetic patients, but its effects on DR in type 1 diabetes have not been reported. This study evaluated the efficacy of fenofibrate on DR in type 1 diabetes models and determined if the effect is PPARα dependent. Oral administration of fenofibrate significantly ameliorated retinal vascular leakage and leukostasis in streptozotocin-induced diabetic rats and in Akita mice. Favorable effects on DR were also achieved by intravitreal injection of fenofibrate or another specific PPARα agonist. Fenofibrate also ameliorated retinal NV in the oxygen-induced retinopathy (OIR) model and inhibited tube formation and migration in cultured endothelial cells. Fenofibrate also attenuated overexpression of intercellular adhesion molecule-1, monocyte chemoattractant protein-1, and vascular endothelial growth factor (VEGF) and blocked activation of hypoxia-inducible factor-1 and nuclear factor-κB in the retinas of OIR and diabetic models. Fenofibrate’s beneficial effects were blocked by a specific PPARα antagonist. Furthermore, Pparα knockout abolished the fenofibrate-induced downregulation of VEGF and reduction of retinal vascular leakage in DR models. These results demonstrate therapeutic effects of fenofibrate on DR in type 1 diabetes and support the existence of the drug target in ocular tissues and via a PPARα-dependent mechanism.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db11-0413/-/DC1.
See accompanying commentary, p. 36.
- Received March 26, 2011.
- Accepted July 7, 2012.
- © 2013 by the American Diabetes Association.
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