REV-ERBα regulates age-related and oxidative stress-induced degeneration in retinal pigment epithelium via NRF2
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
Affiliations
Shuo Huang
Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA
Chi-Hsiu Liu
Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA
Zhongxiao Wang
Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA
Zhongjie Fu
Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA
William R. Britton
Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA
Alexandra K. Blomfield
Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA
Theodore M. Kamenecka
Department of Molecular Medicine, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL, 33458, USA
Joshua L. Dunaief
F.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, USA
Laura A. Solt
Department 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, USA
Jing Chen
Department 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.
