Enhanced expression of C/EBP homologous protein (CHOP) precedes degeneration of fibrocytes in the lateral wall after acute cochlear mitochondrial dysfunction induced by 3-nitropropionic acid
Enhanced expression of C/EBP homologous protein (CHOP) precedes degeneration of fibrocytes in the lateral wall after acute cochlear mitochondrial dysfunction induced by 3-nitropropionic acid
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DOI：
10.1016/j.neuint.2009.12.008
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发表时间：
2010-02-01
影响因子：
4.2
通讯作者：
Matsunaga, Tatsuo
中科院分区：
文献类型：
--
作者：
Fujinami, Yoshiaki;Mutai, Hideki;Matsunaga, Tatsuo
我们以前报道过，用线粒体毒素3-硝基丙酸（3-NP）治疗大鼠耳蜗，根据药物的量，会导致暂时性或永久性听力损失。此外，耳蜗外侧壁纤维细胞的凋亡，这是维持内淋巴的重要，是在这个动物模型中的主要病理特征。已知3-NP诱导氧化应激以及神经元凋亡。C/EBP同源蛋白基因（chop）是内质网应激诱导的标志基因之一，也被认为参与细胞凋亡。为了阐明3-NP诱导耳蜗纤维细胞凋亡的分子机制，我们研究了3-NP处理后耳蜗外侧壁C/EBP同源蛋白（CHOP）和其他ER应激相关信号分子的时空表达以及凋亡细胞的出现。实时荧光定量PCR结果显示，chop和atf-4基因在6 h内表达显著增加，而grp 78和grp 94等ER应激反应基因的表达没有变化。免疫组化结果显示，3-NP治疗引起CHOP的上调，特别是在If型和IV型纤维细胞，随后在同一局限区域出现末端脱氧核苷酸转移酶介导的dUTP缺口末端标记（TUNEL）阳性凋亡细胞。因此，3-NP诱导的外侧壁纤维细胞凋亡可能是通过诱导CHOP介导的。这些结果有助于阐明耳蜗纤维细胞的病理机制，并可能导致新的治疗策略的发展。(C)2009爱思唯尔有限公司保留所有权利。
We previously reported that treatment of the rat cochlea with a mitochondrial toxin, 3-nitropropionic acid (3-NP), causes temporary to permanent hearing loss depending on the amount of the drug. Furthermore, apoptosis of cochlear lateral wall fibrocytes, which are important for maintaining the endolymph, is a predominant pathological feature in this animal model. 3-NP is known to induce oxidative stress as well as neuronal apoptosis. C/EBP homologous protein gene (chop) is one of the marker genes induced during endoplasmic reticulum (ER) stress, and is also considered to be involved in apoptosis. To elucidate the molecular mechanism of cochlear fibrocyte apoptosis induced by 3-NP, we studied spatiotemporal expression of C/EBP homologous protein (CHOP) and other signaling molecules related to ER stress as well as the appearance of apoptotic cells in the cochlear lateral wall after 3-NP treatment. Quantitative real-time PCR revealed that chop and activating transcription factor 4 gene (atf-4) showed marked increase within 6 h, whereas expression of other ER stress-responsive genes such as grp78 and grp94 did not change. Immunohistochemistry showed that 3-NP treatment caused upregulation of CHOP, especially in type If and type IV fibrocytes, followed by the appearance of terminal deoxynucleotidyl transferase mediated dUTP nick end-labeling (TUNEL)-positive apoptotic cells in the same confined area. Thus, apoptosis of lateral wall fibrocytes induced by 3-NP is likely to be mediated by induction of CHOP. These results contribute clarification of pathological mechanism of cochlear fibrocytes and may lead to development of novel therapeutic strategy for hearing loss. (C) 2009 Elsevier Ltd. All rights reserved.