July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Genetic Ablation and Pharmaceutical Inhibition of Nox4 Protects Against Diabetic Keratopathy
Author Affiliations & Notes
  • Wenxin Zhao
    First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
  • Xian Zhang
    Affliated Eye Hospital of Nanchang University, Nanchang, Jiangxi, China
  • QIUPING LIU
    Affliated Eye Hospital of Nanchang University, Nanchang, Jiangxi, China
  • Li Qin
    First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
  • Jingming Li
    First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
  • Footnotes
    Commercial Relationships   Wenxin Zhao, None; Xian Zhang, None; QIUPING LIU, None; Li Qin, None; Jingming Li, None
  • Footnotes
    Support  NSFC Grants 81460163, 81400427 and 81300786; Young Talent Scholar Grant 2016KJXX-12; FRFCU Grant xjj2015015; RFDP Grant 20133601120012; Research Grant from Shaanxi Science and Technology Department 2016JM8029; Research Grants from Jiangxi Education Department GJJ14094, GJJ13175; Research Grants from Jiangxi Science and Technology Department 20142BDH80005, 20142BAB215029, 20132BAB205024.
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 1803. doi:
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      Wenxin Zhao, Xian Zhang, QIUPING LIU, Li Qin, Jingming Li; Genetic Ablation and Pharmaceutical Inhibition of Nox4 Protects Against Diabetic Keratopathy. Invest. Ophthalmol. Vis. Sci. 2018;59(9):1803.

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

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Abstract

Purpose : Diabetic patients are often at high risk for corneal complications including corneal epithelial dysfunction and sensation defect. Nox4 is a major source of reactive oxygen species (ROS) in the eye. In the present study, we assessed the role of Nox4-derived-ROS in impairment of corneal epithelial integrity and reduction of sensory nerve density during diabetic keratopathy (DK).

Methods : Diabetes was induced by intraperitoneal injection of streptozocin in both Nox4 deficent (Nox4-/-) and wild type (Nox4+/+) mice. GKT137831, the Nox1/Nox4 inhibitor, was administrated by rodent diet. Tear secretion, corneal epithelial integrity and never fiber density were determined by cotton thread, fluorescence staining, and in vivo confocal microscopy. Corneal ROS production was measured by Cellrox staining. E-Cadherin, the major component of adherent junction, and NF-κB, the master regulator of inflammatory gene expression, were examined by immunofluorescence or western-blot analysis. Corneal nerve fiber density was examined by flatmount staining with TUBB3 antibody. Expression of inflammatory cytokines including IL-1β, IL-6 and MCP-1 were analyzed by Q-PCR.

Results : Sixteen-week after onset of diabetes, Nox4+/+ mice showed significant decrease of tear secretion, stronger corneal fluorescence staining and dramatic reduction of innervations. Theses alterations were reversed in diabetic Nox4-/- mice or GKT137831-treated mice. Meanwhile, increased ROS production and disrupted E-cadherin expression were observed in corneal epithelia of diabetic Nox4+/+ mice compared with non-diabetic Nox4+/+ mice. However, genetic depletion or pharmaceutical inhibition of Nox4 significantly attenuated diabetes-induced ROS production and corneal E-cadherin disruption. Moreover, Nox4 deletion or inhibition suppressed NF-κB expression and inflammatory gene transcription in diabetic corneal epithelia. Lastly, flatmount staining revealed that density of TUBB3-positive nerve fiber were remarkably reduced in diabetic Nox4+/+ mice, which was markedly prevented by Nox4 deficiency or GKT137831 treatment.

Conclusions : Taken together, Nox4-derived ROS contributed to disruption of epithelial integrity in diabetic corneas likely through NF-κB-mediated inflammatory response. Additionally, genetic or pharmaceutical targeting Nox4 may potentially serve as a promising therapeutic approach for DK intervention.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

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