Journal
JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS
Volume 36, Issue 10, Pages 754-764Publisher
MARY ANN LIEBERT, INC
DOI: 10.1089/jop.2020.0068
Keywords
blood-retina barrier; diabetic retinopathy; fenofibrate; lipoprotein; oxidized LDL; retinal pigment epithelium
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Funding
- Oklahoma Center for the Advancement of Science and Technology [HR08-067]
- Centers of Biomedical Research Excellence Program of the National Center for Research Resources [P20 RR 024215]
- LINJO fund
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Purpose: There is a lack of treatment for early diabetic retinopathy (DR), including blood-retina barrier (BRB) breakdown. The robust clinical benefit of fenofibrate in DR provides an opportunity to explore disease mechanisms and therapeutic targets. We have previously found that modified lipoproteins contribute to DR and that fenofibrate protects the inner BRB. We now investigate (1) whether modified lipoproteins elicit outer BRB injury and (2) whether fenofibrate may alleviate such damage. Methods: Human retinal pigment epithelium ARPE-19 cells were cultured in semipermeable transwells to establish a monolayer barrier and then exposed to heavily oxidized, glycated low-density lipoprotein (HOG-LDL, 25-300 mg/L, up to 24 h) versus native (N)-LDL. Transepithelial electric resistance (TEER) and FITC-dextran permeability were measured. The effects of fenofibrate, its active metabolite fenofibric acid, and other peroxisome proliferator-activated receptor (PPAR alpha) agonists (gemfibrozil, bezafibrate, and WY14643) were evaluated, with and without the PPAR alpha antagonist GW6471 or the adenosine monophosphate-activated protein kinase (AMPK) inhibitor Compound C. Results: HOG-LDL induced concentration- and time-dependent barrier impairment, decreasing TEER and increasing dextran leakage, effects that were amplified by high glucose. Fenofibric acid, but not fenofibrate, gemfibrozil, bezafibrate, or WY14643, attenuated barrier impairment. This effect was reversed significantly by Compound C, but not by GW6471. Conclusions: Modified lipoproteins elicited outer BRB injury in an experimental model, which was reduced by fenofibric acid through a PPAR alpha-independent, AMPK-mediated mechanism. These findings suggest a protective role of fenofibric acid on the outer BRB in diabetic retina.
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