DB19-0898R2 Supplemental Figure.pdf (3.23 MB)

Pathogenic role of PPARα down-regulation in corneal nerve degeneration and impaired corneal sensitivity in diabetes

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posted on 25.03.2020 by Ada Admin, Greg Matlock, Fangfang Qiu, Volha Malechka, Kelu Zhou, Rui Cheng, Siribhinya Benyajati, Amy Whelchel, Dimitrios Karamichos, Jian-xing Ma
The purpose of this study was to investigate the protective role of Peroxisome Proliferator‐Activated Receptor‐alpha (PPARα) against diabetic keratopathy and corneal neuropathy. Corneal samples were obtained from diabetic and non-diabetic human donors. Streptozotocin-induced diabetic rats and mice were orally treated with PPARα agonist fenofibrate. As shown by immunohistochemistry and Western blotting, PPARα was down-regulated in the corneas of diabetic humans and rats. Immunostaining of β-III tubulin demonstrated that corneal nerve fiber metrics were decreased significantly in diabetic rats and mice, which was partially prevented by fenofibrate treatment. As evaluated using a Cochet-Bonnet aesthesiometer, corneal sensitivity was significantly decreased in diabetic mice, which was prevented by fenofibrate. PPARα-/- mice displayed progressive decreases in the corneal nerve fiber density. Consistently, corneal sensitivity was decreased in PPARα-/- mice relative to wild-type mice by nine months of age. Diabetic mice showed increased incidence of spontaneous corneal epithelial lesion, which was prevented by fenofibrate while exacerbated by PPARα knockout. Western blot analysis revealed significantly altered neurotrophic factor levels in diabetic rat corneas, which were partially restored by fenofibrate treatment. These results indicate that PPARα protects corneal nerve from degeneration induced by diabetes, and PPARα agonists have therapeutic potential in the treatment of diabetic keratopathy.

Funding

This study was supported by National Institutes of Health (NIH) grants (EY018659, EY019309, EY012231, EY028949, GM122744), a Juvenile Diabetes Research Foundation (JDRF) grant (2-SRA-2019-711-S-B), and an Oklahoma Center for the Advancement of Science and Technology (OCAST) grant (HR16-041).

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