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

IF 5.4 Q1 GERIATRICS & GERONTOLOGY NPJ Aging and Mechanisms of Disease Pub Date : 2020-12-14 DOI:10.1038/s41514-020-00053-4
Tetsuya Oishi, Daisuke Matsumaru, Nao Ota, Hiroshi Kitamura, Tianxiang Zhang, Yohei Honkura, Yukio Katori, Hozumi Motohashi
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引用次数: 15

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 (Keap1FA/FA) mice, in which KEAP1, a negative regulator of NRF2, is decreased, resulting in the elevation of NRF2 activity. We compared 12-month-old Keap1FA/FA mice with age-matched wild-type (WT) mice in the same breeding colony. In the Keap1FA/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 Keap1FA/FA mice. Auditory brainstem response (ABR) thresholds in the Keap1FA/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 Keap1FA/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.

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在keap1基因敲低的小鼠中,NRF2通路的激活可减缓年龄相关性听力损失的进展。
年龄相关性听力损失(AHL)是老年人进行性感音神经性听力损失。虽然目前还没有针对AHL的预防和治疗方法,但最近的研究表明,氧化应激与AHL的发病密切相关,表明抑制氧化应激可抑制AHL的进展。NRF2是调控多种抗氧化蛋白和细胞保护因子的主转录因子。为了研究NRF2通路激活是否能预防AHL,我们使用KEAP1敲低(Keap1FA/FA)小鼠,在这些小鼠中,NRF2的负调节因子KEAP1减少,导致NRF2活性升高。我们将12月龄Keap1FA/FA小鼠与同一繁殖群体中年龄匹配的野生型(WT)小鼠进行了比较。在Keap1FA/FA小鼠中,证实多个NRF2靶基因的表达水平显著高于这些基因在WT小鼠中的表达水平。组织学分析表明,Keap1FA/FA小鼠耳蜗尖部和中部退行性变得到改善。Keap1FA/FA小鼠的听觉脑干反应(ABR)阈值显著低于WT小鼠,特别是在中低频。免疫组化检测氧化应激标志物提示Keap1FA/FA耳蜗氧化应激积累减弱。因此,我们得出结论,NRF2通路的激活保护耳蜗在衰老过程中免受氧化损伤,特别是在耳蜗的顶端和中间弯。keap1抑制药物和植物化学物质有望有效预防AHL。
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NPJ Aging and Mechanisms of Disease
NPJ Aging and Mechanisms of Disease Medicine-Geriatrics and Gerontology
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期刊介绍: npj Aging and Mechanisms of Disease is an online open access journal that provides a forum for the world’s most important research in the fields of aging and aging-related disease. The journal publishes papers from all relevant disciplines, encouraging those that shed light on the mechanisms behind aging and the associated diseases. The journal’s scope includes, but is not restricted to, the following areas (not listed in order of preference): • cellular and molecular mechanisms of aging and aging-related diseases • interventions to affect the process of aging and longevity • homeostatic regulation and aging • age-associated complications • translational research into prevention and treatment of aging-related diseases • mechanistic bases for epidemiological aspects of aging-related disease.
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