Quercetin induces the expression of peroxiredoxins 3 and 5 via the Nrf2/NRF1 transcription pathway

The flavonoids have potent antioxidant and free-radical scavenging properties and are beneficial in the prevention and treatment of ocular diseases including glaucoma. The authors have previously reported that antiglaucoma agents could transcriptionally activate the antioxidant protein peroxiredoxin...

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Veröffentlicht in:Investigative ophthalmology & visual science 2011-02, Vol.52 (2), p.1055-1063
Hauptverfasser: Miyamoto, Naoya, Izumi, Hiroto, Miyamoto, Rie, Kondo, Hiroyuki, Tawara, Akihiko, Sasaguri, Yasuyuki, Kohno, Kimitoshi
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container_issue 2
container_start_page 1055
container_title Investigative ophthalmology & visual science
container_volume 52
creator Miyamoto, Naoya
Izumi, Hiroto
Miyamoto, Rie
Kondo, Hiroyuki
Tawara, Akihiko
Sasaguri, Yasuyuki
Kohno, Kimitoshi
description The flavonoids have potent antioxidant and free-radical scavenging properties and are beneficial in the prevention and treatment of ocular diseases including glaucoma. The authors have previously reported that antiglaucoma agents could transcriptionally activate the antioxidant protein peroxiredoxin (PRDX)2. The purpose of this study was to investigate whether quercetin can activate transcription factors and induce the expression of the PRDX family. To demonstrate whether quercetin can transcriptionally induce the expression of the PRDX family, trabecular meshwork cells were treated with quercetin, and PRDX expression and transcription factors were both investigated by Western blot analysis, reporter assays, and siRNA strategies. Subsequently, cellular sensitivity to oxidative stress was determined. Expression of the PRDX3 and PRDX5 genes was induced by quercetin in a time- and dose-dependent manner. NRF1 transactivates the promoter activity of both PRDX3 and PRDX5 but not PRDX2 and PRDX4. Quercetin can also induce the expression of Nrf2 and NRF1 but not of Ets1, Ets2, or Foxo3a. Knockdown of NRF1 expression significantly reduced the expression of both PRDX3 and PRDX5. Reporter assays showed that NRF1 transactivated the promoter activity of both PRDX3 and PRDX5 and that the downregulation of NRF1 with siRNA repressed the promoter activity of both PRDX3 and PRDX5. Furthermore, the downregulation of NRF1, PRDX3, and PRDX5 renders trabecular meshwork cells sensitive to hydrogen peroxide. Finally, NRF1 activation by quercetin was completely abolished by the knockdown of Nrf2. Quercetin upregulates the antioxidant peroxiredoxins through the activation of the Nrf2/NRF1 transcription pathway and protects against oxidative stress-induced ocular disease.
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The authors have previously reported that antiglaucoma agents could transcriptionally activate the antioxidant protein peroxiredoxin (PRDX)2. The purpose of this study was to investigate whether quercetin can activate transcription factors and induce the expression of the PRDX family. To demonstrate whether quercetin can transcriptionally induce the expression of the PRDX family, trabecular meshwork cells were treated with quercetin, and PRDX expression and transcription factors were both investigated by Western blot analysis, reporter assays, and siRNA strategies. Subsequently, cellular sensitivity to oxidative stress was determined. Expression of the PRDX3 and PRDX5 genes was induced by quercetin in a time- and dose-dependent manner. NRF1 transactivates the promoter activity of both PRDX3 and PRDX5 but not PRDX2 and PRDX4. Quercetin can also induce the expression of Nrf2 and NRF1 but not of Ets1, Ets2, or Foxo3a. Knockdown of NRF1 expression significantly reduced the expression of both PRDX3 and PRDX5. Reporter assays showed that NRF1 transactivated the promoter activity of both PRDX3 and PRDX5 and that the downregulation of NRF1 with siRNA repressed the promoter activity of both PRDX3 and PRDX5. Furthermore, the downregulation of NRF1, PRDX3, and PRDX5 renders trabecular meshwork cells sensitive to hydrogen peroxide. Finally, NRF1 activation by quercetin was completely abolished by the knockdown of Nrf2. 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Knockdown of NRF1 expression significantly reduced the expression of both PRDX3 and PRDX5. Reporter assays showed that NRF1 transactivated the promoter activity of both PRDX3 and PRDX5 and that the downregulation of NRF1 with siRNA repressed the promoter activity of both PRDX3 and PRDX5. Furthermore, the downregulation of NRF1, PRDX3, and PRDX5 renders trabecular meshwork cells sensitive to hydrogen peroxide. Finally, NRF1 activation by quercetin was completely abolished by the knockdown of Nrf2. 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subjects Antioxidants - pharmacology
Blotting, Western
Cell Line
Dose-Response Relationship, Drug
Electrophoresis, Polyacrylamide Gel
Gene Expression Regulation, Enzymologic - physiology
Gene Silencing
Humans
NF-E2-Related Factor 2 - metabolism
Nuclear Respiratory Factor 1 - metabolism
Oxidative Stress
Peroxiredoxin III
Peroxiredoxins - genetics
Plasmids
Quercetin - pharmacology
RNA, Small Interfering - genetics
Time Factors
Trabecular Meshwork - drug effects
Trabecular Meshwork - enzymology
title Quercetin induces the expression of peroxiredoxins 3 and 5 via the Nrf2/NRF1 transcription pathway
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