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PLoS One. 2019 Feb 4;14(2):e0208399. doi: 10.1371/journal.pone.0208399. eCollection 2019.

Neuroprotective effects of PPARα in retinopathy of type 1 diabetes.

Author information

1
Angiogenesis Laboratory, Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA, United States.
2
Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States.
3
Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States.
4
Department of Biochemistry, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States.
5
EyeCRO LLC, Oklahoma City, OK, United States.
6
Harold Hamm Oklahoma Diabetes Center, Oklahoma City, OK, United States.

Abstract

Diabetic retinopathy (DR) is a common neurovascular complication of type 1 diabetes. Current therapeutics target neovascularization characteristic of end-stage disease, but are associated with significant adverse effects. Targeting early events of DR such as neurodegeneration may lead to safer and more effective approaches to treatment. Two independent prospective clinical trials unexpectedly identified that the PPARα agonist fenofibrate had unprecedented therapeutic effects in DR, but gave little insight into the physiological and molecular mechanisms of action. The objective of the present study was to evaluate potential neuroprotective effects of PPARα in DR, and subsequently to identify the responsible mechanism of action. Here we reveal that activation of PPARα had a robust protective effect on retinal function as shown by Optokinetic tracking in a rat model of type 1 diabetes, and also decreased retinal cell death, as demonstrated by a DNA fragmentation ELISA. Further, PPARα ablation exacerbated diabetes-induced decline of visual function as demonstrated by ERG analysis. We further found that PPARα improved mitochondrial efficiency in DR, and decreased ROS production and cell death in cultured retinal neurons. Oxidative stress biomarkers were elevated in diabetic Pparα-/- mice, suggesting increased oxidative stress. Mitochondrially mediated apoptosis and oxidative stress secondary to mitochondrial dysfunction contribute to neurodegeneration in DR. Taken together, these findings identify a robust neuroprotective effect for PPARα in DR, which may be due to improved mitochondrial function and subsequent alleviation of energetic deficits, oxidative stress and mitochondrially mediated apoptosis.

Conflict of interest statement

We note that two of the authors, Alexander B. Quiambao and Rafal A. Farjo are Employed by a commercial company, EyeCRO LLC. EyeCRO did not play a role in study design, data collection and analysis, preparation of the manuscript, or decision to publish the manuscript. The only financial support provided was for the authors’ salaries. This affiliation does not alter our adherence to PLOS ONE policies regarding sharing data and materials, and the raw data is now available on the Harvard Dataverse. There are no patents, products in development or marketed products related to this work.

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