Nox3-Derived Superoxide in Cochleae Induces Sensorineural Hearing Loss.
Nox3-Derived Superoxide in Cochleae Induces Sensorineural Hearing Loss.
复制标题
耳蜗中的NOX3衍生的超氧化物会诱导感觉神经性听力损失。
DOI：
10.1523/jneurosci.2672-20.2021
复制
发表时间：
2021-05-26
期刊：
影响因子：
--
通讯作者：
Ueyama T
中科院分区：
文献类型：
--
作者：
Mohri H;Ninoyu Y;Sakaguchi H;Hirano S;Saito N;Ueyama T
NADPH氧化酶（Nox）产生的活性氧（ROS）有助于不同类型的感音神经性听力损失（SNHL）的发展，这是一种常见的人类损伤，尚无成熟的治疗方法。尽管在啮齿类动物中已经报道了Nox3在耳蜗生物合成中的重要作用及其可能与听力有关，但针对检测内耳细胞中Nox3表达的免疫组织学方法显示了不明确的结果。因此，nox3依赖性SNHL的机制尚不清楚，需要进一步研究。我们产生了Nox3-Cre敲入小鼠，其中Nox3被Cre重组酶（Cre）取代。使用Nox3-Cre;在tdTomato在Nox3启动子控制下表达的小鼠中，我们确定了内耳中Nox3的表达区域和细胞类型。耳蜗内表达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的表达随顺铂、年龄和噪音损伤而增加。此外，Nox3在支持细胞和外毛细胞中的表达增加，特别是在耳蜗基底部，在ros相关的SNHL中发挥了重要作用。Nox3在SNHL中的参与程度依次为：顺铂性听力损失>年龄相关性听力损失>噪声性听力损失。这里，在Nox3-Cre的基础上；tdTomato可以作为报告系统（Nox3- cre +/−；tdTomato+/+和Nox3- cre +/+；tdTomato+/+）和Nox3- ko （Nox3- cre +/+;tdTomato+/+）小鼠，我们证明耳蜗抑制Nox3是一种很有希望的策略，用于ros相关的SNHL，如顺铂诱导的HL，年龄相关性HL和噪声诱导的HL。我们利用Nox3-Cre在内耳，特别是耳蜗中发现了nox3的表达区和细胞类型；td番茄小鼠，本研究生成的一个报告系统。在耳蜗特定细胞类型中，Nox3的表达随顺铂、年龄和噪声损伤而增加，并导致外毛细胞的丢失（凋亡）。因此，Nox3可能作为一种分子靶点，用于开发治疗感音神经性听力损失的药物，特别是顺铂诱导的、年龄相关的和噪声诱导的听力损失。
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 Nox3-Cre knock-in mice, in which Nox3 was replaced with Cre recombinase (Cre). Using Nox3-Cre;tdTomato mice of either sex, in which tdTomato is expressed under the control of the Nox3 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 Nox3-Cre;tdTomato, which can be used as a reporter system (Nox3-Cre+/−;tdTomato+/+ and Nox3-Cre+/+;tdTomato+/+), and Nox3-KO (Nox3-Cre+/+;tdTomato+/+) 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. SIGNIFICANCE STATEMENT We found Nox3-expressing regions and cell types in the inner ear, especially in the cochlea, using Nox3-Cre;tdTomato 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.
影响因子：
2.4
作者：
Malkemper EP;Mason MJ;Kagerbauer D;Nimpf S;Keays DA
通讯作者：
Keays DA