Pathogenic Role Of Ppar Alpha Downregulation In Corneal Nerve Degeneration And Impaired Corneal Sensitivity In Diabetes

The purpose of this study was to investigate the protective role of peroxisome proliferator-activated receptor alpha (PPAR alpha) against diabetic keratopathy and corneal neuropathy. Corneal samples were obtained from human donors with and without diabetes. Streptozotocin-induced diabetic rats and mice were orally treated with PPAR alpha agonist fenofibrate. As shown by immunohistochemistry and Western blotting, PPAR alpha was downregulated in the corneas of humans with diabetes and diabetic rats. Immunostaining of beta-III tubulin demonstrated that corneal nerve fiber metrics were decreased significantly in diabetic rats and mice, which were 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. PPAR alpha(-/-) mice displayed progressive decreases in the corneal nerve fiber density. Consistently, corneal sensitivity was decreased in PPAR alpha(-/-) mice relative to wild-type mice by 21 months of age. Diabetic mice showed increased incidence of spontaneous corneal epithelial lesion, which was prevented by fenofibrate while exacerbated by PPAR alpha 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 PPAR alpha protects the corneal nerve from degeneration induced by diabetes, and PPAR alpha agonists have therapeutic potential in the treatment of diabetic keratopathy.