Therapeutic Effects of PPARα Agonists on Diabetic Retinopathy in Type 1 Diabetes Models

被引:144
作者
Chen, Ying [1 ,2 ]
Hu, Yang [1 ,2 ]
Lin, Mingkai [1 ,2 ,3 ]
Jenkins, Alicia J. [2 ,4 ]
Keech, Anthony C. [5 ]
Mott, Robert [1 ]
Lyons, Timothy J. [2 ]
Ma, Jian-xing [1 ,2 ]
机构
[1] Univ Oklahoma, Hlth Sci Ctr, Dept Physiol, Oklahoma City, OK 73190 USA
[2] Univ Oklahoma, Hlth Sci Ctr, Harold Hamm Diabet Ctr, Oklahoma City, OK USA
[3] Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, Guangzhou 510275, Guangdong, Peoples R China
[4] Univ Melbourne, Dept Med, Melbourne, Vic, Australia
[5] Univ Sydney, Natl Hlth & Med Research Council Clin Trials Ctr, Sydney, NSW 2006, Australia
基金
美国国家卫生研究院;
关键词
OXYGEN-INDUCED RETINOPATHY; GROWTH-FACTOR; VASCULAR LEAKAGE; FENOFIBRATE; HYPERLIPOPROTEINEMIA; CELLS; MODULATION;
D O I
10.2337/db11-0413
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Retinal vascular leakage, inflammation, and neovascularization (NV) are features of diabetic retinopathy (DR). Fenofibrate, a peroxisome proliferator-activated receptor alpha (PPAR alpha) 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 PPAR alpha 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 PPAR alpha 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-kappa B in the retinas of OIR and diabetic models. Fenofibrate's beneficial effects were blocked by a specific PPAR alpha antagonist. Furthermore, Ppar alpha 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 PPAR alpha-dependent mechanism. Diabetes 62:261-272, 2013
引用
收藏
页码:261 / 272
页数:12
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