Pathogenic Role of PPARα Downregulation in Corneal Nerve Degeneration and Impaired Corneal Sensitivity in Diabetes

Abstract

The purpose of this study was to investigate the protective role of peroxisome proliferator–activated receptor α (PPARα) 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 PPARα agonist fenofibrate. As shown by immunohistochemistry and Western blotting, PPARα was downregulated in the corneas of humans with diabetes and diabetic rats. Immunostaining of β-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. 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 21 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 the corneal nerve from degeneration induced by diabetes, and PPARα agonists have therapeutic potential in the treatment of diabetic keratopathy.

Diabetic Corneal Neuropathy

“…Oral administration of fenofibrate protected the corneal nerves from degeneration in streptozotocin-induced diabetic rats and mice [135].…”

PPARα Modulation-Based Therapy in Central Nervous System Diseases

“…Fenofibrate treatment reduced a loss of corneal nerve fiber density in streptozotocin-induced diabetic rats [104]. In mice, Pparα knockout showed decreases in corneal nerve fiber density and corneal sensitivity and an increase in the incidence of corneal lesions at the chronic stage [104]. These data suggest that targeting PPARα may potentially protect against corneal degeneration induced by diabetes and/or aging.…”

“…In the disease state of corneal diseases, the therapeutic roles of PPARα activation have been studied. In the streptozotocin-induced diabetic rat cornea and diabetic human cornea, a decrease in PPARα expression was detected [104], implying that the functions of PPARα in the cornea could be impaired by diabetes. Fenofibrate treatment reduced a loss of corneal nerve fiber density in streptozotocin-induced diabetic rats [104].…”

“…In the streptozotocin-induced diabetic rat cornea and diabetic human cornea, a decrease in PPARα expression was detected [104], implying that the functions of PPARα in the cornea could be impaired by diabetes. Fenofibrate treatment reduced a loss of corneal nerve fiber density in streptozotocin-induced diabetic rats [104]. In mice, Pparα knockout showed decreases in corneal nerve fiber density and corneal sensitivity and an increase in the incidence of corneal lesions at the chronic stage [104].…”

Diabetic Corneal Neuropathy: Pathogenic Mechanisms and Therapeutic Strategies

“…A drug in one of the fibrate classes, fenofibrate, is a PPARα agonist used to treat abnormal blood lipid levels. Knockout of PPARα in T1D mice and rats aggravated the reduction in corneal nerve fiber density and lowering in corneal sensitivity, which could be prevented by fenofibrate ( Matlock et al, 2020 ).…”