Nrf2 signaling is impaired in the aging RPE given an oxidative insult

• Published in: Experimental eye research 2014-02, Vol.119, p.111-114
• Main Authors: Sachdeva, Mira M., Cano, Marisol, Handa, James T.
• Format: Article
• Language: English
• Subjects: age-related macular degeneration; aging; Aging - metabolism; Animals; Humans; Macular Degeneration - metabolism; Macular Degeneration - pathology; NF-E2-Related Factor 2 - metabolism; Nrf2; oxidative stress; Oxidative Stress - physiology; retinal pigment epithelium; Retinal Pigment Epithelium - metabolism; Retinal Pigment Epithelium - pathology; Signal Transduction
• ISSN: 0014-4835; 1096-0007
• DOI: 10.1016/j.exer.2013.10.024

Age-related macular degeneration (AMD) represents the leading cause of blindness in the elderly, yet no definitive therapy exists for early, dry disease. Several lines of evidence have implicated oxidative stress-induced damage to the retinal pigment epithelium (RPE) in the pathogenesis of AMD, suggesting that the aging RPE may exhibit increased susceptibility to cell damage induced by exogenous stressors. The transcription factor Nrf2 serves as the master regulator of a highly coordinated antioxidant response in virtually all cell types. We compared Nrf2 signaling in the RPE of young (2 months) and old (15 months) mice under unstressed and stressed (sodium iodate) conditions. The aging RPE expressed higher levels of the Nrf2 target genes NQO1, GCLM, and HO1 compared with the RPE of younger mice under unstressed conditions, suggesting an age-related increase in basal oxidative stress. Moreover, the RPE of older mice demonstrated impaired induction of the protective Nrf2 pathway following oxidative stress induced with sodium iodate. The RPE of old mice exposed to sodium iodate also exhibited higher levels of superoxide anion and malondialdehyde than young mice, suggesting inadequate protection against oxidative damage. Induction of Nrf2 signaling in response to sodium iodate was partially restored in the RPE of aging mice with genetic rescue, using conditional knockdown of the Nrf2 negative regulator Keap1 (Tam-Cre; Keap1loxP) compared to Keap1loxP mice. These data indicate that the aging RPE is vulnerable to oxidative damage due to impaired Nrf2 signaling, and that Nrf2 signaling is a promising target for novel pharmacologic or genetic therapeutic strategies. •Nrf2 mediated transcription by the RPE of young and old mice was compared.•Aging RPE had elevated superoxide and malondialdehyde after sodium iodide compared to young RPE.•Aging RPE expressed higher basal levels of NQO1, GCLM, and HO1 than young RPE.•Aging RPE exhibited impaired induction of NQO1, GCLM, and HO1 after sodium iodide.•Genetic rescue by Keap1 knockdown in old mice restored NQO1 expression in the RPE.