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R. Miyamoto, N. Miyamoto, H. Izumi, K. Kohno, A. Tawara; Quercetin Induces the Expression of Peroxiredoxin 3 and 5 Through Nrf2/NRF1 Transcription Pathway. Invest. Ophthalmol. Vis. Sci. 2010;51(13):6120.
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© ARVO (1962-2015); The Authors (2016-present)
Flavonoids such as quercetin can protect various cells from oxidative stress through a variety of mechanisms. Quercetin is one of the most widely distributed flavonoids, present in fruit, vegetables, and many other dietary sources. It has been shown that certain flavonoid can induce antioxidant responsive element (ARE) dependent gene expression through the activation of NF-E2-related factor (Nrf2). Oxidative stress plays an important role in the pathogenesis of various ocular diseases including glaucoma.We have previously shown that oxidative stress can induce peroxiredoxin (PRDX) 1 and 5 through the activation of Ets-1 transcription factor. Further, we have reported that antiglaucoma agents transcriptionally upregulate PRDX2 gene through Foxo3a activation. Thus, several transcription factors can regulate each PRDX genes.The purpose of this study is to investigate whether quercetin can activate the transcription system and induce the gene expression of antioxidant protein.
Trabecular meshwork cells were treated with quercetin. The gene expression of peroxiredoxins and transcription factors were investigated by western blot, reporter assays and siRNA strategy. Cellular sensitivity against oxidative stress was also determined with the WST8-assays.
The expression of both PRDX3 and 5 genes was induced by quercetin in time- and dose-dependent manner. NRF1 transactivates the promoter activity of both PRDX3 and 5 but not PRDX2 and 4 genes. Quercetin can also induce the expression of both Nrf2 and NRF1 but not Ets-1, Ets-2 and Foxo3a. Knockdown of NRF1 expression significantly reduced the expression of both PRDX3 and 5. Reporter assays also showed that NRF1 transactivated the promoter activity of both PRDX3 and 5 genes and down-regulation of NRF1 by siRNA repressed the promoter activity of both PRDX3 and 5 genes. Further, down-regulation of NRF1, PRDX3 and 5 render trabecular meshwork cells sensitive to hydrogen peroxide. Finally, we confirmed that NRF1 activation by quercetin was completely abolished by the knockdown of Nrf2.
Quercetin upregulates the antioxidant peroxiredoxins through the activation of Nrf2/NRF1 transcription system in the trabecular meshwork cells and could protect oxidative stress-induced ocular diseases.
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