A New Mouse Model of Age-Related Ocular Disease (Tet-mev-1 Transgenic Mice) Oxidative Stress-Induced Ocular Change

Abstract

Purpose: : Recently, much attention has focused on the role of oxidative stress in ocular disease, for example, corneal disease such as dry eye and retinal disease such as age-related macular degeneration. The most oxidative stress in cells originates in superoxide anion (O₂^-) generated from mitochondria electron transmission system. We have constructed Tet-mev-1 conditional transgenic mice with a point mutation (V69E) in cytochrome b large subunit (SDHC) of mitochondria electron transmission system complex II. The Tet-mev-1 mice can overproduce O₂^- and the amount of the O₂^- production can be arbitrarily controlled by Tetracycline. Therefore, it is suggested that Tet-mev-1 mice will be a suitable model to clarify molecular mechanism of ocular diseases related with O₂^- of mitochondria by the measurements of oxidative stress in ocular cells.

Methods: : O₂^- measurement were performed on Tet-mev-1 mice of three-month age. Histopathological analysis : Hematoxylin-eosin stainings, nuclear stainings were performed. Immunohistochemistry ( 8-OHdG, β-catenin ) were performed. Detection of apoptosis : TUNEL stainings, c-caspase-3 stainings were performed. The study was conducted in compliance with the ARVO statement for the use of animals in Ophthalmic and Visual Research.

Results: : O₂^- production in the Tet-mev-1 mice of three-month age increased compared to the same aged wild type mice. 8- OHdG as a maker of oxidized DNA increased in corneal epithelium of the Tet-mev-1 mice of six-month age compared with wild type although there was not difference between Tet-mev-1 and wild type mice of three-month age. In addition, a decrease in the thickness of cornea was observed the Tet-mev-1 mice of ten-month age, and this decrease was equivalent to that of wild type of 22-33-month age. The number of corneal endothelial cells of Tet-mev-1 mice also decreased. This was equivalent to that of wild type of twenty four-month age, suggested the decrease of intercellular adhesion ability of corneal endothelial cells in Tet-mev-1 mice at the early stage.

Conclusions: : Further analysis to know whether these phenomena are related with induction of apoptosis and inflammatory cytokine are in progress. Our results suggest that O₂^- from mitochondria would influence pathogenesis or progression of age-related ocular diseases.

Keywords: oxidation/oxidative or free radical damage • cornea: endothelium • aging