REV-ERBα regulates age-related and oxidative stress-induced degeneration in retinal pigment epithelium via NRF2
Retinal pigment epithelium (RPE) dysfunction and atrophy occur in dry age-related macular degeneration (AMD), often leading to photoreceptor degeneration and vision loss. Accumulated oxidative stress during aging contributes to RPE dysfunction and degeneration. Here we show that the nuclear receptor...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2022-05-01
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| Series: | Redox Biology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231722000337 |
| _version_ | 1828432291166158848 |
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| author | Shuo Huang Chi-Hsiu Liu Zhongxiao Wang Zhongjie Fu William R. Britton Alexandra K. Blomfield Theodore M. Kamenecka Joshua L. Dunaief Laura A. Solt Jing Chen |
| author_facet | Shuo Huang Chi-Hsiu Liu Zhongxiao Wang Zhongjie Fu William R. Britton Alexandra K. Blomfield Theodore M. Kamenecka Joshua L. Dunaief Laura A. Solt Jing Chen |
| author_sort | Shuo Huang |
| collection | DOAJ |
| description | Retinal pigment epithelium (RPE) dysfunction and atrophy occur in dry age-related macular degeneration (AMD), often leading to photoreceptor degeneration and vision loss. Accumulated oxidative stress during aging contributes to RPE dysfunction and degeneration. Here we show that the nuclear receptor REV-ERBα, a redox sensitive transcription factor, protects RPE from age-related degeneration and oxidative stress-induced damage. Genetic deficiency of REV-ERBα leads to accumulated oxidative stress, dysfunction and degeneration of RPE, and AMD-like ocular pathologies in aging mice. Loss of REV-ERBα exacerbates chemical-induced RPE damage, and pharmacological activation of REV-ERBα protects RPE from oxidative damage both in vivo and in vitro. REV-ERBα directly regulates transcription of nuclear factor erythroid 2-related factor 2 (NRF2) and its downstream antioxidant enzymes superoxide dismutase 1 (SOD1) and catalase to counter oxidative damage. Moreover, aged mice with RPE specific knockout of REV-ERBα also exhibit accumulated oxidative stress and fundus and RPE pathologies. Together, our results suggest that REV-ERBα is a novel intrinsic protector of the RPE against age-dependent oxidative stress and a new molecular target for developing potential therapies to treat age-related retinal degeneration. |
| first_indexed | 2024-12-10T18:17:50Z |
| format | Article |
| id | doaj.art-d3c8835aceba4b349400a9c669a90905 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-12-10T18:17:50Z |
| publishDate | 2022-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-d3c8835aceba4b349400a9c669a909052022-12-22T01:38:18ZengElsevierRedox Biology2213-23172022-05-0151102261REV-ERBα regulates age-related and oxidative stress-induced degeneration in retinal pigment epithelium via NRF2Shuo Huang0Chi-Hsiu Liu1Zhongxiao Wang2Zhongjie Fu3William R. Britton4Alexandra K. Blomfield5Theodore M. Kamenecka6Joshua L. Dunaief7Laura A. Solt8Jing Chen9Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USADepartment of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USADepartment of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USADepartment of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USADepartment of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USADepartment of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USADepartment of Molecular Medicine, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL, 33458, USAF.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, 305 Stellar-Chance Laboratory, 422 Curie Blvd, Philadelphia, PA, 19104, USADepartment of Immunology and Microbiology, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL, 33458, USA; Department of Molecular Medicine, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL, 33458, USADepartment of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA; Corresponding author.Retinal pigment epithelium (RPE) dysfunction and atrophy occur in dry age-related macular degeneration (AMD), often leading to photoreceptor degeneration and vision loss. Accumulated oxidative stress during aging contributes to RPE dysfunction and degeneration. Here we show that the nuclear receptor REV-ERBα, a redox sensitive transcription factor, protects RPE from age-related degeneration and oxidative stress-induced damage. Genetic deficiency of REV-ERBα leads to accumulated oxidative stress, dysfunction and degeneration of RPE, and AMD-like ocular pathologies in aging mice. Loss of REV-ERBα exacerbates chemical-induced RPE damage, and pharmacological activation of REV-ERBα protects RPE from oxidative damage both in vivo and in vitro. REV-ERBα directly regulates transcription of nuclear factor erythroid 2-related factor 2 (NRF2) and its downstream antioxidant enzymes superoxide dismutase 1 (SOD1) and catalase to counter oxidative damage. Moreover, aged mice with RPE specific knockout of REV-ERBα also exhibit accumulated oxidative stress and fundus and RPE pathologies. Together, our results suggest that REV-ERBα is a novel intrinsic protector of the RPE against age-dependent oxidative stress and a new molecular target for developing potential therapies to treat age-related retinal degeneration.http://www.sciencedirect.com/science/article/pii/S2213231722000337Retinal pigment epitheliumAgingAge-related macular degenerationREV-ERBαOxidative damageNRF2 |
| spellingShingle | Shuo Huang Chi-Hsiu Liu Zhongxiao Wang Zhongjie Fu William R. Britton Alexandra K. Blomfield Theodore M. Kamenecka Joshua L. Dunaief Laura A. Solt Jing Chen REV-ERBα regulates age-related and oxidative stress-induced degeneration in retinal pigment epithelium via NRF2 Redox Biology Retinal pigment epithelium Aging Age-related macular degeneration REV-ERBα Oxidative damage NRF2 |
| title | REV-ERBα regulates age-related and oxidative stress-induced degeneration in retinal pigment epithelium via NRF2 |
| title_full | REV-ERBα regulates age-related and oxidative stress-induced degeneration in retinal pigment epithelium via NRF2 |
| title_fullStr | REV-ERBα regulates age-related and oxidative stress-induced degeneration in retinal pigment epithelium via NRF2 |
| title_full_unstemmed | REV-ERBα regulates age-related and oxidative stress-induced degeneration in retinal pigment epithelium via NRF2 |
| title_short | REV-ERBα regulates age-related and oxidative stress-induced degeneration in retinal pigment epithelium via NRF2 |
| title_sort | rev erbα regulates age related and oxidative stress induced degeneration in retinal pigment epithelium via nrf2 |
| topic | Retinal pigment epithelium Aging Age-related macular degeneration REV-ERBα Oxidative damage NRF2 |
| url | http://www.sciencedirect.com/science/article/pii/S2213231722000337 |
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