Fenofibrate prevents the disruption of the outer blood retinal barrier through downregulation of NF-κB activity

Marta Garcia-Ramírez, Cristina Hernández, Xavier Palomer, Manuel Vázquez-Carrera, Rafael Simó

Research output: Contribution to journalArticleResearchpeer-review

17 Citations (Scopus)

Abstract

© 2015, Springer-Verlag Italia. Aims: 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.
Original languageEnglish
Pages (from-to)109-118
JournalActa Diabetologica
Volume53
Issue number1
DOIs
Publication statusPublished - 1 Feb 2016

Keywords

  • Cytokines
  • Diabetic macular edema
  • Fenofibrate
  • Inflammation
  • NF-κB
  • Retinal pigment epithelium

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