MATE1 expression in the cochlea and its potential involvement in cisplatin cellular uptake and ototoxicity

Abstract

Background

Cisplatin appears to enter the cochlear cells through the organic cation transporter 2 (OCT2). There is recent evidence that multidrug and toxin extrusion protein 1 (MATE1) is involved in cisplatin-induced nephrotoxicity. Its presence and role in the ear are unknown.

Aims/Objectives

Evaluate the presence and localization of MATE1, and determine the localization of OCT2, in the cochlea. Evaluate cisplatin uptake with regard to MATE1 and OCT2 expression.

Material and Methods

Murine cochlear explants and paraffin-embedded cochleae were evaluated with immunohistochemistry for OCT2 and MATE1. Explant cultures were also treated with Texas Red cisplatin to determine their cellular uptake.

Results

MATE1 is present in the cochlea. Most intense labeling of MATE1 and OCT2 was seen in the outer hair cells (OHCs) and pillar cells, respectively. Both transporters were observed in the spiral ganglion neurons and stria vascularis. Expression levels of OCT2 and MATE1 decreased following cisplatin exposure. Texas Red cisplatin staining was strong in OHCs and pillar cells.

Conclusions and Significance

To the best of our knowledge, this is the first study demonstrating the presence and localization of MATE1 in the cochlea. OCT2 labeling was seen in pillar cells. Consistently, OHCs and pillar cells uptake Texas Red cisplatin.

Chinese Abstract

背景：顺铂似乎通过有机阳离子转运蛋白 2 （OCT2）进入耳蜗细胞。 最近有证据表明多药和毒素挤压蛋白 1 (MATE1) 参与顺铂引起的肾毒性。 它在耳朵中的存在和作用是未知的。

目的：评估耳蜗中MATE1 的存在和定位, 并确定OCT2定位。 评估顺铂在 MATE1 和 OCT2 表达方面的摄取。

材料和方法：对小鼠耳蜗外植体和石蜡包埋耳蜗进行了OCT2 和 MATE1 的免疫组织化学方面的评估。 外植体培养物也用德克萨斯红顺铂来处理, 以确定它们的细胞摄取。

结果：MATE1 存在于耳蜗中。 MATE1 和 OCT2 的最强烈标记分别见于外毛细胞 (OHC) 和柱状细胞。 在螺旋神经节神经元和血管纹中观察到两种转运蛋白。 顺铂接触后 OCT2 和 MATE1 的表达水平降低。 得克萨斯红顺铂染色在 OHC 和柱状细胞中很强。

结论和意义：据我们所知, 这是证明MATE1 在耳蜗中的存在和定位的首项研究。 在柱状细胞中观察到 OCT2 标记。 与此相应地, OHC 和柱状细胞摄取德克萨斯红顺铂。

Keywords:

• OCT2
• MATE
• MATE1
• cisplatin
• platinum
• ototoxicity
• transporters
• organic cation transporter
• pillar cell
• outer hair cell

Disclosure statement

The authors report there are no competing interests to declare.

Additional information

Funding

Funding was provided by Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT-ANID) grants 11201142 for SW, and 1171240 for ADM; Fondo Nacional de Investigación en Salud (FONIS-FONDEF SA18I0194) for HS; the Chilean Millennium Centro Interdisciplinario de Neurociencia de Valparaíso grant P09-022F for ADM and HS, and Fundacion Guillermo Puelma for JCM.