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Effect of fenofibrate on retinal neurodegeneration in an experimental model of type 2 diabetes

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Abstract

There is now consistent evidence from two major clinical trials (the Fenofibrate Intervention and Event Lowering in Diabetes and the Action to Control Cardiovascular Risk in Diabetes Eye) that fenofibrate arrests the progression of diabetic retinopathy in type 2 diabetic patients. However, the underlying mechanisms of this beneficial effect remain to be elucidated. The aim of the study was to evaluate the potential effect of fenofibric acid (FA), the active metabolite of fenofibrate, in preventing retinal neurodegeneration in an experimental mouse model of type 2 diabetes. For this purpose, we evaluated a total of 24 diabetic mice (db/db) aged 8 weeks that were randomly assigned to daily oral treatment (by gavage) with FA (100 mg/kg/day) (n = 12) or vehicle (n = 12) for 1 week. Ten non-diabetic mice (db/+) were used as control group. Retinal neurodegeneration was evaluated by measuring glial activation (immunofluorescence and Western blot) and apoptosis. Glutamate/aspartate transporter (GLAST) was assessed by immunofluorescence. Functional abnormalities were assessed by electroretinography (ERG). We observed that diabetic mice presented significantly higher glial activation and apoptosis in ganglion cell layer (GCL) than in age-matched non-diabetic mice. Treatment with FA resulted in a significant decrease in both glial activation and the rate of apoptosis in GCL in comparison with diabetic mice treated with vehicle. In addition, FA prevented GLAST downregulation induced by diabetes. Furthermore, a significant improvement of ERG parameters (oscillatory potential amplitudes and b-wave implicit time) was observed. We conclude that FA prevents retinal neurodegeneration induced by diabetes. Our results suggest that neuroprotection is one of the underlying mechanisms by which fenofibrate exerts its beneficial actions in diabetic retinopathy.

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Abbreviations

ACCORD:

The Action to Control Cardiovascular Risk in Diabetes

DR:

Diabetic retinopathy

FA:

Fenofibric acid

ERG:

Electroretinography

FIELD:

Fenofibrate Intervention and Event Lowering in Diabetes

GDNF:

Glial Cell Line-Derived Neurotrophic Factor

GCL:

Ganglion cell layer

GLAST:

Glutamate–aspartate transporter

GFAP:

Glial fibrillar acidic protein

H&E:

Hematoxylin and eosin

ISCEV:

International Society for Clinical Electrophysiology of Vision

Lp-PLA2:

Lipoprotein-associated phospholipase A2

OIR:

Oxygen-induced retinopathy

ONL:

Outer nuclear layer

OPs:

Oscillatory potentials

PPAR:

Peroxisome proliferator-activated receptor

RPE:

Retinal pigment epithelium

TUNEL:

Terminal Transferase dUTP Nick-End Labeling

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Acknowledgments

We thank Abbott for providing us with fenofibric acid (FA). This study was supported by grants from the Ministerio de Ciencia e Innovación (SAF2012-35562), the European Foundation for the Study of Diabetes (EFSD), and the Generalitat de Catalunya (SGR2009-739).

Conflict of interest

None.

Human and animal rights

This article does not contain any studies with human subjects performed by any of the authors. All the animal experiments were performed in accordance with the protocol approved by the Animal Care and Use Committee of Vall d’Hebron Research Institute (VHIR) and Association for Research in Vision and Ophthalmology (ARVO).

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Authors and Affiliations

  1. Diabetes and Metabolism Research Unit, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona, Pg. Vall d’Hebron 119-129, 08035, Barcelona, Spain

    Patricia Bogdanov, Cristina Hernández, Lidia Corraliza & Rafael Simó

  2. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain

    Patricia Bogdanov, Cristina Hernández, Lidia Corraliza & Rafael Simó

  3. Ophthalmologic Research Laboratory, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain

    Andrea R. Carvalho

  4. Red de Investigación Colaborativa en Oftalmología, ISCIII, Madrid, Spain

    Andrea R. Carvalho

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  1. Patricia Bogdanov
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  2. Cristina Hernández
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  3. Lidia Corraliza
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  4. Andrea R. Carvalho
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  5. Rafael Simó
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Correspondence to Rafael Simó.

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Managed by Massimo Federici.

Patricia Bogdanov and Cristina Hernández have contributed equally to this work.

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Bogdanov, P., Hernández, C., Corraliza, L. et al. Effect of fenofibrate on retinal neurodegeneration in an experimental model of type 2 diabetes. Acta Diabetol 52, 113–122 (2015). https://doi.org/10.1007/s00592-014-0610-2

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