April 2011
Volume 52, Issue 14
Free
ARVO Annual Meeting Abstract  |   April 2011
Mechanisms for the Therapeutic Effect of Fenofibrate on Diabetic Retinopathy in Type 1 Diabetes Models
Author Affiliations & Notes
  • Ying Chen
    Physiology,
    OUHSC, Oklahoma City, Oklahoma
  • Yang Hu
    Physiology,
    OUHSC, Oklahoma City, Oklahoma
  • Robert Mott
    Physiology,
    OUHSC, Oklahoma City, Oklahoma
  • Scott Mitchell
    Physiology,
    OUHSC, Oklahoma City, Oklahoma
  • Mingkai Lin
    Ophthalmology, Zhonshan Ophthalmic Center, Guangzhou, China
  • Kevin Zhou
    Physiology,
    OUHSC, Oklahoma City, Oklahoma
  • Alicia Jenkins
    Medicine, The University of Melbourne, Melbourne, Australia
  • Anthony Keech
    National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia
  • Timothy Lyons
    Medicine,
    OUHSC, Oklahoma City, Oklahoma
  • Jian-xing Ma
    Physiology,
    OUHSC, Oklahoma City, Oklahoma
  • Footnotes
    Commercial Relationships  Ying Chen, None; Yang Hu, None; Robert Mott, None; Scott Mitchell, None; Mingkai Lin, None; Kevin Zhou, None; Alicia Jenkins, None; Anthony Keech, None; Timothy Lyons, None; Jian-xing Ma, None
  • Footnotes
    Support  EY018659, EY012231, EY019309, P20RR024215 and ADA
Investigative Ophthalmology & Visual Science April 2011, Vol.52, 2100. doi:
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      Ying Chen, Yang Hu, Robert Mott, Scott Mitchell, Mingkai Lin, Kevin Zhou, Alicia Jenkins, Anthony Keech, Timothy Lyons, Jian-xing Ma; Mechanisms for the Therapeutic Effect of Fenofibrate on Diabetic Retinopathy in Type 1 Diabetes Models. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2100.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : Retinal vascular leakage, inflammation, and neovascularization are features of diabetic retinopathy (DR), a common cause of vision loss. Our previous studies demonstrate that over-activation of the Wnt pathway promotes DR, and that fenofibrate can ameliorate DR in clinical studies of type 2 diabetes patients. As yet there are no studies in type 1 diabetes, nor understanding of the molecular mechanism for the fenofibrate’s retinopathy benefit, hence we evaluated the efficacy of fenofibrate on DR in type 1 diabetes models and elucidated the underlying mechanisms.

Methods: : Oxygen-induced retinopathy (OIR) rats, streptozotocin (STZ) diabetic TOPGAL mice and Akita TOPGAL mice were orally administrated or intravitreally injected with fenofibrate. Retinal vascular permeability, retinal vascular leukostasis, and retinal inflammation were evaluated. Wnt pathway activation was evaluated by beta gal staining and by measurement the levels of phosphorylation of low-density lipoprotein receptor-related protein 6 (LRP6), and non phosphorylated β-catenin, an effector of the canonical Wnt pathway. REC or RPE were exposed to a medium containing Wnt 3A ligand in the presence or absence of various doses of fenofibrate. Wnt pathway activities were evaluated by TOPFLASH assay and by measurement the levels of LRP6 and non-phosphorylated β-catenin.

Results: : In STZ-induced diabetic rats and Akita mice diabetic type 1 diabetic models, oral administration of fenofibrate significantly reduced retinal vascular permeability, retinal vascular leukostasis and retinal inflammation. Intraocular injection of fenofibrate also robustly reduced retinal vascular leakage and inflammation in the diabetic models, suggesting that the fenofibrate effects are not dependent on systemic effects. Intravitreal injection of fenofibrate also inhibited ischemia-induced retinal neovascularization in OIR rats. In the retina of diabetic animals and in cultured retinal cells, fenofibrate significantly inhibited phosphorylation of LRP6, and attenuated accumulation, and transcriptional activity of β-catenin.

Conclusions: : These results support that fenofibrate can ameliorate DR in type 1 diabetes via blockade of Wnt pathway activation in the diabetic retina.

Keywords: inflammation • retina • receptors: pharmacology/physiology 
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