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

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Abstract

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.

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Acknowledgments

We thank Abbott for providing us with fenofibric acid (FA). This study was supported by grants from the Generalitat de Catalunya (2014-SGR-270), the Spanish Ministerio de Economía y Competitividad (SAF2012-30708), European Union ERDF funds, and from CIBERDEM (CIBER de Diabetes y Enfermedades Metabólicas Asociadas). CIBERDEM is an initiative of the Instituto de Salud Carlos III.

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Human and Animal Rights

This article does not contain any studies with human or animal subjects performed by any of the authors.

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Informed consent was obtained from all individual participants included in the study.

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Correspondence to Rafael Simó.

Additional information

Managed by Massimo Federici.

Marta Garcia-Ramírez and Cristina Hernández have contributed equally to this work.

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Garcia-Ramírez, M., Hernández, C., Palomer, X. et al. Fenofibrate prevents the disruption of the outer blood retinal barrier through downregulation of NF-κB activity. Acta Diabetol 53, 109–118 (2016). https://doi.org/10.1007/s00592-015-0759-3

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  • DOI: https://doi.org/10.1007/s00592-015-0759-3

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