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Transient acceleration of autophagic degradation by pharmacological Nrf2 activation is important for retinal pigment epithelium cell survival.
Redox Biol. 2018 10; 19:354-363.RB

Abstract

Non-exudative age-related macular degeneration (AMD) is mainly caused by the accumulation of lipofuscin and drusen on the retinal pigment epithelium (RPE). Both oxidative stress and autophagic dysfunction accelerate the deposition of lipofuscin at the RPE. One of the key regulators in the response against oxidative stress is the NF-E2-Related Factor 2 (Nrf2)-kelch like ECH associated protein 1 (Keap1) axis, which is also closely associated with the autophagy pathway. Nrf2 activation upregulates the expression levels of certain anti-oxidative enzymes [e.g. Heme oxygenase-1 (HO-1)], which attenuates oxidative damage. However, until now, the relationship between cytoprotective effects of Nrf2 activation and autophagic degradation remain unclear. To address these questions, we investigated the effects of a novel Nrf2 activator, RS9, on RPE damage. We found that RS9 protected ARPE-19 cells against NaIO3-induced oxidative damage, and that the protective effects of RS9 were inhibited by co-treatment with zinc protoporphyrin, an HO-1 inhibitor. Next, we examined the involvement of autophagic degradation in the protective effects of RS9. Co-treatment with RS9 and chloroquine, a lysosomal acidification inhibitor, inhibited the protective effect. Furthermore, western blotting and immunostaining showed that RS9 accelerated autophagy flux and induced transient upregulation of p62 [also known as sequestosome 1 (SQSTM1)]. Co-treatment with chloroquine and RS9 also inhibited the degradation of autophagosomes. Transient upregulation of SQSTM1 by RS9 was unaltered by HO-1 knockdown using siRNA. RS9 and chloroquine had the same actions in light damaged adult zebrafish retina as those in vitro. In conclusion, we clarified the relationship between acceleration of the autophagy pathway and the cytoprotective effects of Nrf2 activation in RPE cells and zebrafish retina. These findings indicated that Nrf2 activation could be a promising therapeutic approach for non-exudative AMD by supporting RPE maintenance.

Authors+Show Affiliations

Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, 1-25-4 Daigakunishi, Gifu 501-1196, Japan.Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, 1-25-4 Daigakunishi, Gifu 501-1196, Japan.Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, 1-25-4 Daigakunishi, Gifu 501-1196, Japan.Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, 1-25-4 Daigakunishi, Gifu 501-1196, Japan. Electronic address: nakamuras@gifu-pu.ac.jp.Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, 1-25-4 Daigakunishi, Gifu 501-1196, Japan. Electronic address: hidehara@gifu-pu.ac.jp.Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, 1-25-4 Daigakunishi, Gifu 501-1196, Japan. Electronic address: shimazawa@gifu-pu.ac.jp.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30216854

Citation

Saito, Yuichi, et al. "Transient Acceleration of Autophagic Degradation By Pharmacological Nrf2 Activation Is Important for Retinal Pigment Epithelium Cell Survival." Redox Biology, vol. 19, 2018, pp. 354-363.
Saito Y, Kuse Y, Inoue Y, et al. Transient acceleration of autophagic degradation by pharmacological Nrf2 activation is important for retinal pigment epithelium cell survival. Redox Biol. 2018;19:354-363.
Saito, Y., Kuse, Y., Inoue, Y., Nakamura, S., Hara, H., & Shimazawa, M. (2018). Transient acceleration of autophagic degradation by pharmacological Nrf2 activation is important for retinal pigment epithelium cell survival. Redox Biology, 19, 354-363. https://doi.org/10.1016/j.redox.2018.09.004
Saito Y, et al. Transient Acceleration of Autophagic Degradation By Pharmacological Nrf2 Activation Is Important for Retinal Pigment Epithelium Cell Survival. Redox Biol. 2018;19:354-363. PubMed PMID: 30216854.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Transient acceleration of autophagic degradation by pharmacological Nrf2 activation is important for retinal pigment epithelium cell survival. AU - Saito,Yuichi, AU - Kuse,Yoshiki, AU - Inoue,Yuki, AU - Nakamura,Shinsuke, AU - Hara,Hideaki, AU - Shimazawa,Masamitsu, Y1 - 2018/09/05/ PY - 2018/05/30/received PY - 2018/08/28/revised PY - 2018/09/03/accepted PY - 2018/9/15/pubmed PY - 2018/12/12/medline PY - 2018/9/15/entrez KW - Autophagy KW - NF-E2-related factor 2 KW - Non-exudative age-related macular degeneration KW - Retinal pigment epithelium KW - Sequestosome 1 SP - 354 EP - 363 JF - Redox biology JO - Redox Biol VL - 19 N2 - Non-exudative age-related macular degeneration (AMD) is mainly caused by the accumulation of lipofuscin and drusen on the retinal pigment epithelium (RPE). Both oxidative stress and autophagic dysfunction accelerate the deposition of lipofuscin at the RPE. One of the key regulators in the response against oxidative stress is the NF-E2-Related Factor 2 (Nrf2)-kelch like ECH associated protein 1 (Keap1) axis, which is also closely associated with the autophagy pathway. Nrf2 activation upregulates the expression levels of certain anti-oxidative enzymes [e.g. Heme oxygenase-1 (HO-1)], which attenuates oxidative damage. However, until now, the relationship between cytoprotective effects of Nrf2 activation and autophagic degradation remain unclear. To address these questions, we investigated the effects of a novel Nrf2 activator, RS9, on RPE damage. We found that RS9 protected ARPE-19 cells against NaIO3-induced oxidative damage, and that the protective effects of RS9 were inhibited by co-treatment with zinc protoporphyrin, an HO-1 inhibitor. Next, we examined the involvement of autophagic degradation in the protective effects of RS9. Co-treatment with RS9 and chloroquine, a lysosomal acidification inhibitor, inhibited the protective effect. Furthermore, western blotting and immunostaining showed that RS9 accelerated autophagy flux and induced transient upregulation of p62 [also known as sequestosome 1 (SQSTM1)]. Co-treatment with chloroquine and RS9 also inhibited the degradation of autophagosomes. Transient upregulation of SQSTM1 by RS9 was unaltered by HO-1 knockdown using siRNA. RS9 and chloroquine had the same actions in light damaged adult zebrafish retina as those in vitro. In conclusion, we clarified the relationship between acceleration of the autophagy pathway and the cytoprotective effects of Nrf2 activation in RPE cells and zebrafish retina. These findings indicated that Nrf2 activation could be a promising therapeutic approach for non-exudative AMD by supporting RPE maintenance. SN - 2213-2317 UR - https://www.unboundmedicine.com/medline/citation/30216854/Transient_acceleration_of_autophagic_degradation_by_pharmacological_Nrf2_activation_is_important_for_retinal_pigment_epithelium_cell_survival_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S2213-2317(18)30455-5 DB - PRIME DP - Unbound Medicine ER -