July 2019
Volume 60, Issue 9
Free
ARVO Annual Meeting Abstract  |   July 2019
Elucidating the role of peroxisome proliferator-activated receptor alpha in diabetic keratopathy using novel in vivo and in vitro models
Author Affiliations & Notes
  • Amy Whelchel
    University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Greg Matlock
    University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Jian-Xing (Jay) Ma
    University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Dimitrios Karamichos
    University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Footnotes
    Commercial Relationships   Amy Whelchel, None; Greg Matlock, None; Jian-Xing (Jay) Ma, None; Dimitrios Karamichos, None
  • Footnotes
    Support  NH Grant EY028949
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 3234. doi:
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      Amy Whelchel, Greg Matlock, Jian-Xing (Jay) Ma, Dimitrios Karamichos; Elucidating the role of peroxisome proliferator-activated receptor alpha in diabetic keratopathy using novel in vivo and in vitro models. Invest. Ophthalmol. Vis. Sci. 2019;60(9):3234.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Peroxisome proliferator-activated receptor alpha (PPARα) has been established as a strong contributor in the regulation of many metabolic diseases, including diabetes. About half of the diabetic population will exhibit corneal defects, commonly known as diabetic keratopathy, yet PPARα remains uninvestigated in the cornea. Our group has begun the investigation of PPARα using novel PPARα KO mouse models and a 3D innervated in vitro model, in an effort to elucidate the mechanisms that relate PPARα to the pathology of diabetic keratopathy.

Methods : Ex vivo: Corneal tissue samples from healthy donors, and Type I / Type II diabetic donors were collected, and PPARα expression was examined through immunohistochemistry (IHC), western blot (WB) and real time RT-PCR. In vivo: PPARα KO mice in C57/BL6J background were originally purchased from Jackson lab. Nerve fiber density, corneal sensitivity and corneal lesions were measured and compared to the WT controls. In vitro: Human corneal fibroblasts from healthy and diabetic corneal samples were isolated and cultured on polycarbonate membranes with media containing stable VitC to promote extracellular matrix (ECM) production. After 4 weeks, PPARα expression was investigated, using real time RT-PCR and WB.

Results : Ex vivo: IHC revealed that diabetic human corneas exhibit down-regulation of PPARα expression when compared to healthy controls. Down-regulation of PPARα was further confirmed by both WB and RT-PCR. In vivo: PPARα KO mice exhibited significantly higher occurrences of spontaneous corneal ulcers, as well as significantly decreased corneal nerve fiber density and corneal sensitivity when compared to the WT controls. In vitro: In agreement to our ex vivo data, constructs grown from diabetic corneal fibroblasts exhibited decreased expression of PPARα when compared to those grown from healthy corneal fibroblasts.

Conclusions : Our group is the first to examine PPARα levels in the diabetic cornea. Our ex vivo, in vivo and in vitro results confirm that PPARα is a key player to the pathophysiology involved in diabetic keratopathy. Furthermore, the spontaneous corneal erosion developed in the PPARα KO mice is a significant development in our efforts towards discovering novel therapeutic targets.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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