TY - JOUR
T1 - Pathogenic role of PPARα downregulation in corneal nerve degeneration and impaired corneal sensitivity in diabetes
AU - Matlock, H. Greg
AU - Qiu, Fangfang
AU - Malechka, Volha
AU - Zhou, Kelu
AU - Cheng, Rui
AU - Benyajati, Siribhinya
AU - Whelchel, Amy
AU - Karamichos, Dimitrios
AU - Ma, Jian Xing
N1 - Funding Information:
Acknowledgments. Shrestha Priyadarsini (Dean McGee Eye Institute, Oklahoma City, OK) prepared the human cornea samples used for immunolabeling. The authors thank the Diabetic Animal Core and Histology Core facilities of Diabetes CoBRE for the support of and assistance in this study. Funding. This study was supported by National Eye Institute grants (EY018659, EY019309, EY012231, EY028949, and GM122744), JDRF grant (2-SRA-2019-711-S-B), and an Oklahoma Center for the Advancement of Science and Technology grant (HR16-041). Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. H.G.M., D.K., and J.-x.M. designed the experiments. H.G.M. conducted the experiments, researched data, and drafted the manuscript. H.G.M., F.Q., V.M., K.Z., R.C., and A.W. assisted with dissections and final grading of corneal lesions. S.B., D.K., and J.-x.M. reviewed and edited the manuscript. All authors approved the final version of the manuscript. J.-x.M. is the guarantor of this work and, as such, has full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Publisher Copyright:
© 2020 by the American Diabetes Association.
PY - 2020/6/1
Y1 - 2020/6/1
N2 - 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. PPARa‒/‒ mice displayed progressive decreases in the corneal nerve fiber density. Consistently, corneal sensitivity was decreased in PPARa‒/‒ 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 PPARa 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.
AB - 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. PPARa‒/‒ mice displayed progressive decreases in the corneal nerve fiber density. Consistently, corneal sensitivity was decreased in PPARa‒/‒ 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 PPARa 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.
UR - http://www.scopus.com/inward/record.url?scp=85085263783&partnerID=8YFLogxK
U2 - 10.2337/db19-0898
DO - 10.2337/db19-0898
M3 - Article
C2 - 32213513
AN - SCOPUS:85085263783
SN - 0012-1797
VL - 69
SP - 1279
EP - 1291
JO - Diabetes
JF - Diabetes
IS - 6
ER -