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).