Fenofibrate prevents the disruption of the outer blood retinal barrier through downregulation of NF-κB activity.
OBJECTIVE
There is clinical evidence that fenofibrate, a PPARα agonist, arrests the progression of diabetic macular edema (DME). However, the underlying mechanisms of this beneficial effect remain to be elucidated. We previously reported that fenofibric acid (FA), the active metabolite of fenofibrate, prevents the disorganization of tight junction proteins and the hyperpermeability provoked by the diabetic milieu in the retinal pigment epithelium (RPE). The aim of the present study was to evaluate whether this effect is mediated by inhibiting the proinflammatory transcription factor NF-κB, as well as the expression of several proinflammatory cytokines involved in the pathogenesis of DME.


METHODS
Human RPE cells were cultured under standard conditions and under conditions leading to the disruption of the monolayer [IL-1β (10 ng/ml)]. The effect of FA, QNZ (a NF-κB inhibitor), WY14643 (a PPARα agonist), and MK-866 (a PPARα antagonist) in the disruption of the monolayer was determined by dextran permeability and immunohistochemistry analyses. The effect of FA on NF-κB activity was assessed by EMSA and by NF-κB/p65 nuclear translocation analyses. The expression of cytokines (IL-6, IL-8, MCP-1) was measured by RT-PCR.


RESULTS
FA prevented RPE monolayer disruption, and the consequent hyperpermeability induced by IL-1β, through inhibition of NF-κB activity. This effect was due to PPARα activation and was associated with a significant downregulation of the expression of proinflammatory cytokines.


CONCLUSIONS
Our findings suggest that the anti-inflammatory effects of FA through inhibition of NF-κB activity play a key role in the beneficial effect of fenofibrate for treating DME.
Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Pg. Vall d'Hebron 119-129, 08035, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
Marta
M
Garcia-Ramírez
Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Pg. Vall d'Hebron 119-129, 08035, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
Cristina
C
Hernández
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.|Department of Pharmacology and Therapeutic Chemistry and Institute of Biomedicine of the University of Barcelona (IBUB), Faculty of Pharmacy, University of Barcelona, Barcelona, Spain.
Xavier
X
Palomer
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.|Department of Pharmacology and Therapeutic Chemistry and Institute of Biomedicine of the University of Barcelona (IBUB), Faculty of Pharmacy, University of Barcelona, Barcelona, Spain.
Manuel
M
Vázquez-Carrera
Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Pg. Vall d'Hebron 119-129, 08035, Barcelona, Spain. rafael.simo@vhir.org.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. rafael.simo@vhir.org.
Rafael
R
Simó
D001813:Blood-Retinal Barrier / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D002199:Capillary Permeability / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003930:Diabetic Retinopathy / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects; D011345:Fenofibrate / Q000031:analogs & derivatives / Q000494:pharmacology*; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008269:Macular Edema / Q000378:metabolism / Q000473:pathology; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051996:Transcription Factor RelA / Q000378:metabolism*
D016207:Cytokines; D053583:Interleukin-1beta; D015850:Interleukin-6; D051996:Transcription Factor RelA; C006012:fenofibric acid; D011345:Fenofibrate
Cytokines; Diabetic macular edema; Fenofibrate; Inflammation; NF-κB; Retinal pigment epithelium