Therapeutic effects of PPARα agonists on diabetic retinopathy in type 1 diabetes models

Ying Chen, Yang Hu, Mingkai Lin, Alicia Jenkins, Anthony C Keech, Robert Mott, Timothy J Lyons, Jian-xing Ma

Research output: Contribution to journalArticlepeer-review

100 Citations (Scopus)

Abstract

Retinal vascular leakage, inflammation, and neovascularization (NV) are features of diabetic retinopathy (DR). Fenofibrate, a peroxisome proliferator-activated receptor a (PPARa) 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 PPARa 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 PPARa 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-?B in the retinas of OIR and diabetic models. Fenofibrate's beneficial effects were blocked by a specific PPARa antagonist. Furthermore, Ppara 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 PPARa-dependent mechanism.
Original languageEnglish
Pages (from-to)261-72
Number of pages12
JournalDiabetes
Volume62
Issue number1
DOIs
Publication statusPublished - Jan 2013

Keywords

  • Animals
  • Retina
  • Fenofibrate
  • Leukocytes
  • Capillary Permeability
  • Disease Models, Animal
  • Mice
  • PPAR alpha
  • Rats, Inbred BN
  • Rats
  • Diabetic Retinopathy
  • Hypoglycemic Agents
  • Diabetes Mellitus, Type 1
  • Mice, Inbred C57BL
  • Male
  • Cell Adhesion

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