Protective role of Nrf2 in age-related hearing loss and gentamicin ototoxicity.
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 3 months of age, their hearing ability was significantly more impaired than that of age-matched wild-type mice at 6 and 11 months of age. Additionally, the numbers of hair cells and spiral ganglion cells were remarkably reduced in Nrf2-knockout mice at 11 months 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.
Department of Otolaryngology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan. tomofumi@md.tsukuba.ac.jp
Tomofumi
T
Hoshino
Keiji
K
Tabuchi
Bungo
B
Nishimura
Shuho
S
Tanaka
Masahiro
M
Nakayama
Tetsuro
T
Ishii
Eiji
E
Warabi
Toru
T
Yanagawa
Ritsuku
R
Shimizu
Masayuki
M
Yamamoto
Akira
A
Hara
D000375:Aging; D000818:Animals; D000900:Anti-Bacterial Agents / Q000009:adverse effects*; D007758:Ear, Inner / Q000187:drug effects / Q000201:enzymology*; D018507:Gene Expression Regulation, Developmental; D005839:Gentamicins / Q000009:adverse effects*; D006198:Hair Cells, Auditory / Q000187:drug effects / Q000201:enzymology; D034381:Hearing Loss / Q000139:chemically induced* / Q000235:genetics*; D051547:Heme Oxygenase-1 / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000502:physiology*; D020218:Response Elements; D013136:Spiral Ganglion / Q000187:drug effects / Q000201:enzymology; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1
D000900:Anti-Bacterial Agents; D005839:Gentamicins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C000606290:SOD1 protein, human; D051547:Heme Oxygenase-1; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse