Laboratory of Molecular Pharmacology, Biosignal Research Center, Kobe University, Kobe, 657-8501, Japan.
Department of Otolaryngology-Head and Neck Surgery, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan.
J Neurosci. 2021 May 26;41(21):4716-4731. doi: 10.1523/JNEUROSCI.2672-20.2021. Epub 2021 Apr 13.
Reactive oxygen species (ROS) produced by NADPH oxidases (Nox) contribute to the development of different types of sensorineural hearing loss (SNHL), a common impairment in humans with no established treatment. Although the essential role of Nox3 in otoconia biosynthesis and its possible involvement in hearing have been reported in rodents, immunohistological methods targeted at detecting Nox3 expression in inner ear cells reveal ambiguous results. Therefore, the mechanism underlying Nox3-dependent SNHL remains unclear and warrants further investigation. We generated knock-in mice, in which Nox3 was replaced with (). Using mice of either sex, in which tdTomato is expressed under the control of the promoter, we determined Nox3-expressing regions and cell types in the inner ear. Nox3-expressing cells in the cochlea included various types of supporting cells, outer hair cells, inner hair cells, and spiral ganglion neurons. Nox3 expression increased with cisplatin, age, and noise insults. Moreover, increased Nox3 expression in supporting cells and outer hair cells, especially at the basal turn of the cochlea, played essential roles in ROS-related SNHL. The extent of Nox3 involvement in SNHL follows the following order: cisplatin-induced hearing loss > age-related hearing loss > noise-induced hearing loss. Here, on the basis of , which can be used as a reporter system ( and ), and -KO () mice, we demonstrate that Nox3 inhibition in the cochlea is a promising strategy for ROS-related SNHL, such as cisplatin-induced HL, age-related HL, and noise-induced HL. We found Nox3-expressing regions and cell types in the inner ear, especially in the cochlea, using mice, a reporter system generated in this study. Nox3 expression increased with cisplatin, age, and noise insults in specific cell types in the cochlea and resulted in the loss (apoptosis) of outer hair cells. Thus, Nox3 might serve as a molecular target for the development of therapeutics for sensorineural hearing loss, particularly cisplatin-induced, age-related, and noise-induced hearing loss.
活性氧（ROS）由 NADPH 氧化酶（Nox）产生，有助于不同类型的感觉神经性听力损失（SNHL）的发展，这是一种常见的人类损伤，目前尚无既定的治疗方法。尽管 Nox3 在耳石生物合成中的重要作用及其在听力中的可能参与已在啮齿动物中得到报道，但针对内耳细胞中 Nox3 表达的免疫组织化学方法得出的结果并不明确。因此，Nox3 依赖性 SNHL 的机制尚不清楚，需要进一步研究。我们生成了 Nox3 基因敲入小鼠，其中 Nox3 被替换为（）。使用表达 tdTomato 的（）雌雄小鼠，我们确定了内耳中 Nox3 表达的区域和细胞类型。耳蜗中表达 Nox3 的细胞包括各种类型的支持细胞、外毛细胞、内毛细胞和螺旋神经节神经元。Nox3 的表达随着顺铂、年龄和噪声损伤的增加而增加。此外，支持细胞和外毛细胞中 Nox3 表达的增加，尤其是耳蜗基底回，在外毛细胞 ROS 相关的 SNHL 中起关键作用。Nox3 参与 SNHL 的程度如下：顺铂诱导的听力损失>年龄相关性听力损失>噪声诱导的听力损失。在这里，基于可以作为报告系统（和）和 -KO（）小鼠，我们证明了耳蜗中 Nox3 的抑制是一种有前途的策略，可用于治疗与 ROS 相关的 SNHL，例如顺铂诱导的 HL、年龄相关性 HL 和噪声诱导的 HL。我们在内耳，特别是耳蜗中发现了 Nox3 表达的区域和细胞类型，使用了本研究中生成的报告系统。在耳蜗的特定细胞类型中，Nox3 的表达随着顺铂、年龄和噪声损伤的增加而增加，并导致外毛细胞的丧失（凋亡）。因此，Nox3 可能成为治疗感觉神经性听力损失，特别是顺铂诱导的、年龄相关性和噪声诱导的听力损失的分子靶标。
