title: Beneficial effects of fenofibric acid on overexpression of extracellular matrix components, COX-2, and impairment of endothelial permeability associated with diabetic retinopathy.
abstract: In the Fenofibric Acid (FA) Intervention and Event Lowering in Diabetes (FIELD) study, FA, a lipid-lowering drug, has been shown to significantly reduce macular edema in diabetic patients. In the present study, we investigated whether FA reduces vascular permeability by inhibiting cyclooxygenase-2 (COX-2), a critical mediator of inflammation, and reducing overexpression of fibronectin (FN) and collagen IV (Coll IV), two basement membrane (BM) components upregulated in diabetic retinopathy. Rat retinal endothelial cells (RRECs) were grown in normal (N:5 mM glucose) or high glucose (HG:30 mM glucose) medium with or without FA for 7 days. Total protein isolated from these cells was assessed for FN, Coll IV, COX-2, and zonula occludens-1 (ZO-1), a tight junction protein, using Western blot analysis. In addition, the distribution and localization of ZO-1 was determined by immunofluorescence microscopy, and cell monolayer permeability was studied by in vitro permeability (IVP) assay. RRECs grown in HG medium showed significant increase in FN, Coll IV, and COX-2 expression (179%, 144%, 139% of N respectively), and a decrease in ZO-1 expression (48% of N) compared to those of N cells. Cells grown in HG medium supplemented with FA significantly reduced FN, Coll IV, and COX-2 expression by 47%, 32%, and 34% respectively, with concomitant increase in ZO-1 expression by 42%. In parallel studies, IVP assays showed a significant increase (139% of N) in cell monolayer permeability in RRECs grown in HG medium, which was significantly reduced with FA treatment. Additionally, immunostaining results indicated FA prevents HG-induced downregulation of ZO-1. The findings indicate that the beneficial effect of FA in reducing excess permeability is mediated, at least in part, by downregulating abnormal overexpression of BM components and inflammatory factors and preventing compromised tight junctions associated with diabetic retinopathy.
authors: Department of Medicine, Boston University School of Medicine, Boston, MA, USA; Department of Ophthalmology, Boston University School of Medicine, Boston, MA, USA.
authors: Sumon
authors: S
authors: Roy
authors: Department of Medicine, Boston University School of Medicine, Boston, MA, USA; Department of Ophthalmology, Boston University School of Medicine, Boston, MA, USA.
authors: Dongjoon
authors: D
authors: Kim
authors: Diabetes and Metabolism Research Unit, Institut de Recerca, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona (UAB), and CIBERDEM, Barcelona, Spain.
authors: Cristina
authors: C
authors: Hernández
authors: Diabetes and Metabolism Research Unit, Institut de Recerca, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona (UAB), and CIBERDEM, Barcelona, Spain.
authors: Rafael
authors: R
authors: Simó
authors: Department of Medicine, Boston University School of Medicine, Boston, MA, USA; Department of Ophthalmology, Boston University School of Medicine, Boston, MA, USA. Electronic address: sayon@bu.edu.
authors: Sayon
authors: S
authors: Roy
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002199:Capillary Permeability / Q000187:drug effects; D002478:Cells, Cultured; D024141:Collagen Type IV / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D003930:Diabetic Retinopathy / Q000188:drug therapy* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D011345:Fenofibrate / Q000031:analogs & derivatives* / Q000494:pharmacology; D005353:Fibronectins / Q000378:metabolism*; D016650:Fluorescein-5-isothiocyanate / Q000378:metabolism; D019084:Fluorescent Antibody Technique, Indirect; D008856:Microscopy, Fluorescence; D051381:Rats; D012171:Retinal Vessels; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
chemical_list: D000924:Anticholesteremic Agents; D024141:Collagen Type IV; D005353:Fibronectins; C569044:Tjp1 protein, rat; D062826:Zonula Occludens-1 Protein; C006012:fenofibric acid; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D016650:Fluorescein-5-isothiocyanate; D011345:Fenofibrate
keywords: Collagen type IV; Fenofibric acid; Fibronectin; Retinal endothelial cells