Protective role of Nrf2 in age-related hearing loss and gentamicin ototoxicity

• Published in: Biochemical and biophysical research communications 2011-11, Vol.415 (1), p.94-98
• Main Authors: Hoshino, Tomofumi, Tabuchi, Keiji, Nishimura, Bungo, Tanaka, Shuho, Nakayama, Masahiro, Ishii, Tetsuro, Warabi, Eiji, Yanagawa, Toru, Shimizu, Ritsuku, Yamamoto, Masayuki, Hara, Akira
• Format: Article
• Language: English
• Subjects: Age-related hearing loss (AHL); Aging; Animals; Anti-Bacterial Agents - adverse effects; Cochlea; Ear, Inner - drug effects; Ear, Inner - enzymology; Gene Expression Regulation, Developmental; Gentamicin ototoxicity; Gentamicins - adverse effects; Hair Cells, Auditory - drug effects; Hair Cells, Auditory - enzymology; Hearing Loss - chemically induced; Hearing Loss - genetics; Heme Oxygenase-1 - genetics; Mice; Mice, Knockout; NAD(P)H Dehydrogenase (Quinone) - genetics; NF-E2-related factor (Nrf2); NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - physiology; Reactive oxygen species (ROS); Response Elements; Spiral Ganglion - drug effects; Spiral Ganglion - enzymology; Superoxide Dismutase - genetics; Superoxide Dismutase-1
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2011.10.019

► We examined the role of Nrf2 in age-related hearing loss and gentamicin ototoxicity. ► Elder Nrf2-knockout mice have age-related hearing loss. ► Hair cell loss caused by gentamicin treatment was enhanced in the Nrf2-deficient tissues. ► The responses of Nrf2-target genes by gentamicin were reduced in Nrf2-knockout mice. Expression of antioxidant enzymes is regulated by transcription factor NF-E2-related factor (Nrf2) and induced by oxidative stress. Reactive oxygen species contribute to the formation of several types of cochlear injuries, including age-related hearing loss and gentamicin ototoxicity. In this study, we examined the roles of Nrf2 in age-related hearing loss and gentamicin ototoxicity by measuring auditory brainstem response thresholds in Nrf2-knockout mice. Although Nrf2-knockout mice maintained normal auditory thresholds at 3months of age, their hearing ability was significantly more impaired than that of age-matched wild-type mice at 6 and 11months of age. Additionally, the numbers of hair cells and spiral ganglion cells were remarkably reduced in Nrf2-knockout mice at 11months of age. To examine the importance of Nrf2 in protecting against gentamicin-induced ototoxicity, 3-day-old mouse organ of Corti explants were cultured with gentamicin. Hair cell loss caused by gentamicin treatment was enhanced in the Nrf2-deficient tissues. Furthermore, the expressions of some Nrf2-target genes were activated by gentamicin treatment in wild-type mice but not in Nrf2-knockout mice. The present findings indicate that Nrf2 protects the inner ear against age-related hearing injuries and gentamicin ototoxicity by up-regulating antioxidant enzymes and detoxifying proteins.