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J. Cai, L. Wang, Y. chen, P. Sternberg; Upregulation of Nrf2-Dependent Antioxidant Function in the Retina by Dietary Zinc Supplementation. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2973.
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Long-term zinc supplementation, both alone and in conjunction with antioxidant vitamins, can reduce the risk of disease progression in patients with age-related macular degeneration (AMD). Our previous studies in cultured RPE cells demonstrated that zinc upregulated the antioxidant system which was dependent on the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). The purpose of this study was to further characterize the in vivo effects of zinc in mouse retina and RPE.
Wild type C57 BL/6J mice and Nrf2 reporter mice with the same genetic background were fed with either regular or zinc-supplemented diet for 1 month. The Nrf2 reporter mice carry a transgene constructed by inserting the antioxidant response element (ARE) upstream of the human placenta alkaline phosphatase (hPAP) gene. The mRNA levels of hPAP and other antioxidant genes in the retina were quantified by real-time RT-PCR. Changes in the amount of retinal and plasma thiol metabolites were measured by HPLC.
High zinc diet increased the total glutathione contents in the retina of female mice. Zinc upregulated the retinal expression of hPAP and gamma-glutamylcysteine ligase, which is the rate limiting enzyme of glutathione synthesis. Plasma concentrations of total cysteine and glutathione were found to be lower in zinc-treated female mice.
Dietary zinc supplementation can increase Nrf2 activity and upregulate its downstream antioxidant function in the RPE and retina. Such mechanism likely contributes to the protective effects of zinc as reported by the Age-Related Eye Disease Study (AREDS).
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