Activation of the NRF2 pathway in Keap1-knockdown mice attenuates progression of age-related hearing loss

Abstract Age-related hearing loss (AHL) is a progressive sensorineural hearing loss in elderly people. Although no prevention or treatments have been established for AHL, recent studies have demonstrated that oxidative stress is closely related to pathogenesis of AHL, suggesting that suppression of...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Tetsuya Oishi, Daisuke Matsumaru, Nao Ota, Hiroshi Kitamura, Tianxiang Zhang, Yohei Honkura, Yukio Katori, Hozumi Motohashi
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Geriatrics RC952-954.6
Acceso en línea:	https://doaj.org/article/90942eff5eaa478aa91b20376ff615a1
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:90942eff5eaa478aa91b20376ff615a1
record_format	dspace
spelling	oai:doaj.org-article:90942eff5eaa478aa91b20376ff615a12021-12-02T14:19:59ZActivation of the NRF2 pathway in Keap1-knockdown mice attenuates progression of age-related hearing loss10.1038/s41514-020-00053-42056-3973https://doaj.org/article/90942eff5eaa478aa91b20376ff615a12020-12-01T00:00:00Zhttps://doi.org/10.1038/s41514-020-00053-4https://doaj.org/toc/2056-3973Abstract Age-related hearing loss (AHL) is a progressive sensorineural hearing loss in elderly people. Although no prevention or treatments have been established for AHL, recent studies have demonstrated that oxidative stress is closely related to pathogenesis of AHL, suggesting that suppression of oxidative stress leads to inhibition of AHL progression. NRF2 is a master transcription factor that regulates various antioxidant proteins and cytoprotection factors. To examine whether NRF2 pathway activation prevents AHL, we used Keap1-knockdown (Keap1 FA/FA) mice, in which KEAP1, a negative regulator of NRF2, is decreased, resulting in the elevation of NRF2 activity. We compared 12-month-old Keap1 FA/FA mice with age-matched wild-type (WT) mice in the same breeding colony. In the Keap1 FA/FA mice, the expression levels of multiple NRF2 target genes were verified to be significantly higher than the expression levels of these genes in the WT mice. Histological analysis showed that cochlear degeneration at the apical and middle turns was ameliorated in the Keap1 FA/FA mice. Auditory brainstem response (ABR) thresholds in the Keap1 FA/FA mice were significantly lower than those in the WT mice, in particular at low–mid frequencies. Immunohistochemical detection of oxidative stress markers suggested that oxidative stress accumulation was attenuated in the Keap1 FA/FA cochlea. Thus, we concluded that NRF2 pathway activation protects the cochlea from oxidative damage during aging, in particular at the apical and middle turns. KEAP1-inhibiting drugs and phytochemicals are expected to be effective in the prevention of AHL.Tetsuya OishiDaisuke MatsumaruNao OtaHiroshi KitamuraTianxiang ZhangYohei HonkuraYukio KatoriHozumi MotohashiNature PortfolioarticleGeriatricsRC952-954.6ENnpj Aging and Mechanisms of Disease, Vol 6, Iss 1, Pp 1-15 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Geriatrics RC952-954.6
spellingShingle	Geriatrics RC952-954.6 Tetsuya Oishi Daisuke Matsumaru Nao Ota Hiroshi Kitamura Tianxiang Zhang Yohei Honkura Yukio Katori Hozumi Motohashi Activation of the NRF2 pathway in Keap1-knockdown mice attenuates progression of age-related hearing loss
description	Abstract Age-related hearing loss (AHL) is a progressive sensorineural hearing loss in elderly people. Although no prevention or treatments have been established for AHL, recent studies have demonstrated that oxidative stress is closely related to pathogenesis of AHL, suggesting that suppression of oxidative stress leads to inhibition of AHL progression. NRF2 is a master transcription factor that regulates various antioxidant proteins and cytoprotection factors. To examine whether NRF2 pathway activation prevents AHL, we used Keap1-knockdown (Keap1 FA/FA) mice, in which KEAP1, a negative regulator of NRF2, is decreased, resulting in the elevation of NRF2 activity. We compared 12-month-old Keap1 FA/FA mice with age-matched wild-type (WT) mice in the same breeding colony. In the Keap1 FA/FA mice, the expression levels of multiple NRF2 target genes were verified to be significantly higher than the expression levels of these genes in the WT mice. Histological analysis showed that cochlear degeneration at the apical and middle turns was ameliorated in the Keap1 FA/FA mice. Auditory brainstem response (ABR) thresholds in the Keap1 FA/FA mice were significantly lower than those in the WT mice, in particular at low–mid frequencies. Immunohistochemical detection of oxidative stress markers suggested that oxidative stress accumulation was attenuated in the Keap1 FA/FA cochlea. Thus, we concluded that NRF2 pathway activation protects the cochlea from oxidative damage during aging, in particular at the apical and middle turns. KEAP1-inhibiting drugs and phytochemicals are expected to be effective in the prevention of AHL.
format	article
author	Tetsuya Oishi Daisuke Matsumaru Nao Ota Hiroshi Kitamura Tianxiang Zhang Yohei Honkura Yukio Katori Hozumi Motohashi
author_facet	Tetsuya Oishi Daisuke Matsumaru Nao Ota Hiroshi Kitamura Tianxiang Zhang Yohei Honkura Yukio Katori Hozumi Motohashi
author_sort	Tetsuya Oishi
title	Activation of the NRF2 pathway in Keap1-knockdown mice attenuates progression of age-related hearing loss
title_short	Activation of the NRF2 pathway in Keap1-knockdown mice attenuates progression of age-related hearing loss
title_full	Activation of the NRF2 pathway in Keap1-knockdown mice attenuates progression of age-related hearing loss
title_fullStr	Activation of the NRF2 pathway in Keap1-knockdown mice attenuates progression of age-related hearing loss
title_full_unstemmed	Activation of the NRF2 pathway in Keap1-knockdown mice attenuates progression of age-related hearing loss
title_sort	activation of the nrf2 pathway in keap1-knockdown mice attenuates progression of age-related hearing loss
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/90942eff5eaa478aa91b20376ff615a1
work_keys_str_mv	AT tetsuyaoishi activationofthenrf2pathwayinkeap1knockdownmiceattenuatesprogressionofagerelatedhearingloss AT daisukematsumaru activationofthenrf2pathwayinkeap1knockdownmiceattenuatesprogressionofagerelatedhearingloss AT naoota activationofthenrf2pathwayinkeap1knockdownmiceattenuatesprogressionofagerelatedhearingloss AT hiroshikitamura activationofthenrf2pathwayinkeap1knockdownmiceattenuatesprogressionofagerelatedhearingloss AT tianxiangzhang activationofthenrf2pathwayinkeap1knockdownmiceattenuatesprogressionofagerelatedhearingloss AT yoheihonkura activationofthenrf2pathwayinkeap1knockdownmiceattenuatesprogressionofagerelatedhearingloss AT yukiokatori activationofthenrf2pathwayinkeap1knockdownmiceattenuatesprogressionofagerelatedhearingloss AT hozumimotohashi activationofthenrf2pathwayinkeap1knockdownmiceattenuatesprogressionofagerelatedhearingloss
_version_	1718391560874229760

Activation of the NRF2 pathway in Keap1-knockdown mice attenuates progression of age-related hearing loss

Ejemplares similares