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: Sumon Roy, Dongjoon Kim, Cristina Hernández, Rafael Simó, Sayon Roy
• Journal: Experimental eye research (Exp Eye Res) Vol. 140 Pg. 124-129 (Nov 2015) ISSN: 1096-0007 [Electronic] England
• PMID: 26297615 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Anticholesteremic Agents
• Collagen Type IV
• Fibronectins
• Tjp1 protein, rat
• Zonula Occludens-1 Protein
• fenofibric acid
• Cyclooxygenase 2
• Ptgs2 protein, rat
• Fluorescein-5-isothiocyanate
• Fenofibrate

Topics

• Animals
• Anticholesteremic Agents (pharmacology)
• Blotting, Western
• Capillary Permeability (drug effects)
• Cells, Cultured
• Collagen Type IV (metabolism)
• Cyclooxygenase 2 (metabolism)
• Diabetic Retinopathy (drug therapy, metabolism)
• Endothelium, Vascular (drug effects, metabolism)
• Fenofibrate (analogs & derivatives, pharmacology)
• Fibronectins (metabolism)
• Fluorescein-5-isothiocyanate (metabolism)
• Fluorescent Antibody Technique, Indirect
• Microscopy, Fluorescence
• Rats
• Retinal Vessels
• Zonula Occludens-1 Protein (metabolism)