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      Aldose reductase inhibitor counteracts the enhanced expression of matrix metalloproteinase-10 and improves corneal wound healing in galactose-fed rats

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          We investigated the effect of an aldose reductase inhibitor (ARI) and the role of matrix metalloproteinase (MMP)-10 on recovery after corneal epithelium removal in a rat diabetic keratopathy model.


          Three-week-old Sprague-Dawley rats were fed the following diets for 6 weeks: normal MF chow (MF), 50% galactose (Gal), and 50% Gal containing 0.01% ARI (Gal +ARI). The corneal epithelium was removed using n-heptanol, and the area of epithelial defects was photographed and measured every 24 h. Real-time reverse transcriptase PCR, western blotting, and immunohistochemistry were used to determine the expression profile of MMP-10 and integrin α3.


          Compared to the MF control group, the amount of galactitol in the Gal group increased approximately 200-fold, which was reduced to sevenfold by ARI treatment. The area of corneal erosion in the Gal group was significantly larger than in the MF group at 72 h and thereafter (p<0.01, unpaired t test). The expression level of MMP-10 was enhanced at both the protein and mRNA levels by exposure to a high concentration of Gal, while integrin α3 expression decreased at the protein level but remained unchanged at the mRNA level. Delayed epithelial wound healing and alterations in the expression levels of MMP-10 and integrin α3 were normalized by ARI. The corneal erosion closure rate was significantly decreased with topical recombinant MMP-10.


          These studies confirm that the increased expression of MMP-10 induced by Gal feeding is counteracted by ARI treatment and suggest a role of MMP-10 in modulating corneal epithelial wound healing.

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          Most cited references 39

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          Oxidative stress in normal and impaired wound repair.

          A large percentage of the population suffers from wound healing abnormalities, in particular aged individuals, patients with diabetes, and those treated with immunosuppressive drugs, chemo- or radiotherapy. The mechanisms underlying the impaired healing response are still poorly understood. Recent studies provided strong evidence for a role of oxidative stress in the pathogenesis of non-healing ulcers. Therefore, it is of major importance to identify and functionally characterize the factors involved in the generation and detoxification of reactive oxygen species (ROS). This will provide the basis for the development of new strategies for therapeutic intervention. In this review we summarize the current information about the roles of low molecular weight antioxidants and ROS-detoxifying enzymes in normal and impaired wound repair, and we report on the consequences of their modulation at the wound site.
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            Diabetic retinopathy.

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              Demonstration that polyol accumulation is responsible for diabetic cataract by the use of transgenic mice expressing the aldose reductase gene in the lens.

              Aldose reductase (AR) has been implicated in the etiology of diabetic cataract, as well as in other complications. However, the role of AR in these complications remains controversial because the strongest supporting evidence is drawn from the use of AR inhibitors for which specificity in vivo cannot be ascertained. To settle this issue we developed transgenic mice that overexpress AR in their lens epithelial cells and found that they become susceptible to the development of diabetic and galactose cataracts. When the sorbitol dehydrogenase-deficient mutation is also present in these transgenic mice, greater accumulation of sorbitol and further acceleration of diabetic cataract develop. These genetic studies demonstrated convincingly that accumulation of polyols from the reduction of hexose by AR leads to the formation of sugar cataracts.

                Author and article information

                Mol Vis
                Mol. Vis
                Molecular Vision
                Molecular Vision
                08 December 2013
                : 19
                : 2477-2486
                [1 ]Department of Ophthalmology, Faculty of Medical Sciences, University of Fukui, Eiheiji-cho, Yoshida-gun, Fukui, Japan
                [2 ]Dainippon Sumitomo Pharma.Co. Ltd. Drug Development Research Laboratories, Osaka, Japan
                Author notes
                Correspondence to: Yoshihiro Takamura, Department of Ophthalmology, Faculty of Medical Sciences, University of Fukui, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan; Phone: +81-776-61-8403; FAX: +81-776-61-8131; email: ytakamura@ 123456hotmail.com
                246 2013MOLVIS0445
                Copyright © 2013 Molecular Vision.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited, used for non-commercial purposes, and is not altered or transformed.

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