title: Therapeutic effects of PPARα agonists on diabetic retinopathy in type 1 diabetes models.
abstract: 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.
authors.affiliation: Department of Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.forename: Yang
authors.initials: Y
authors.lastname: Hu
authors.forename: Mingkai
authors.initials: M
authors.lastname: Lin
authors.forename: Alicia J
authors.initials: AJ
authors.lastname: Jenkins
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Keech
authors.forename: Robert
authors.initials: R
authors.lastname: Mott
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Lyons
authors.forename: Jian-xing
authors.initials: JX
authors.lastname: Ma
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D003922:Diabetes Mellitus, Type 1 / Q000150:complications*; D003930:Diabetic Retinopathy / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D011345:Fenofibrate / Q000494:pharmacology / Q000627:therapeutic use*; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047493:PPAR alpha / Q000819:agonists* / Q000502:physiology; D051381:Rats; D011914:Rats, Inbred BN; D012160:Retina / Q000187:drug effects / Q000378:metabolism
chemical_list: D007004:Hypoglycemic Agents; D047493:PPAR alpha; D011345:Fenofibrate