1. Academic Validation
  2. Inhibition of Soluble Epoxide Hydrolase 2 Ameliorates Diabetic Keratopathy and Impaired Wound Healing in Mouse Corneas

Inhibition of Soluble Epoxide Hydrolase 2 Ameliorates Diabetic Keratopathy and Impaired Wound Healing in Mouse Corneas

  • Diabetes. 2018 Jun;67(6):1162-1172. doi: 10.2337/db17-1336.
Haijing Sun 1 Patrick Lee 1 Chenxi Yan 1 2 Nan Gao 1 Jiemei Wang 3 Xianqun Fan 2 Fu-Shin Yu 4
Affiliations

Affiliations

  • 1 Departments of Ophthalmology and Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI.
  • 2 Department of Ophthalmology, Shanghai Ninth Peoples' Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
  • 3 Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI.
  • 4 Departments of Ophthalmology and Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI fyu@med.wayne.edu.
Abstract

EPHX2 (encoding soluble Epoxide Hydrolase [sEH]) converts biologically active epoxyeicosatrienoic acids (EETs), anti-inflammatory and profibrinolytic effectors, into the less biologically active metabolites, dihydroxyeicostrienoic acids. We sought to characterize the expression and the function of EPHX2 in diabetic corneas and during wound healing. The expression of EPHX2 at both mRNA and protein levels, as well as sEH enzymatic activity, was markedly upregulated in the tissues/cells, including corneal epithelial cells as well as the retina of human type 2 and mouse type 1 (streptozotocin [STZ] induced) and/or type 2 diabetes. Ephx2 depletion had no detectable effects on STZ-induced hyperglycemia but prevented the development of tear deficiency. Ephx2-/- mice showed an acceleration of hyperglycemia-delayed epithelium wound healing. Moreover, inhibition of sEH increased the rate of epithelium wound closure and restored hyperglycemia-suppressed STAT3 activation and heme oxygenase-1 (HO-1) expression in the diabetic corneas. Treatment of diabetic corneas with cobalt protoporphyrin, a well-known HO-1 inducer, restored wound-induced HO-1 upregulation and accelerated delayed wound healing. Finally, Ephx2 depletion enhanced sensory innervation and regeneration in diabetic corneas at 1 month after epithelial debridement. Our data suggest that increased sEH activity may be a contributing factor for diabetic corneal complications; targeting sEH pharmacologically or supplementing EETs may represent a new, adjunctive therapy for treating diabetic keratopathy.

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