Mukherjea D, Whitworth C A, Nandish S, Dunaway G A, Rybak L P, Ramkumar V
Department of Pharmacology, Southern Illinois University School of Medicine, PO Box 19629, Springfield, IL 62794-9626, USA.
Neuroscience. 2006 May 12;139(2):733-40. doi: 10.1016/j.neuroscience.2005.12.044. Epub 2006 Feb 7.
Cisplatin is a widely used chemotherapeutic agent whose dose-limiting side effects include ototoxicity and nephrotoxicity. Recent evidence indicates that cisplatin induces the expression of a novel protein, kidney injury molecule-1, in the renal proximal tubular epithelium to aid in regeneration. In this study, we determined whether kidney injury molecule-1 is expressed in the cochlea and is induced by cisplatin. Using reverse transcriptase polymerase chain reaction techniques, we have now identified kidney injury molecule-1 in the rat cochlea and in three different mouse transformed hair cell lines. Administration of cisplatin to rats produced hearing loss and induced kidney injury molecule-1 mRNA in the rat cochlea. Pretreatment of rats with lipoic acid, a scavenger of reactive oxygen species, significantly reduced cisplatin-induced hearing loss and kidney injury molecule-1 expression. Cisplatin also increased the expression of cochlear NOX3 mRNA, a member of the superoxide generating NADPH oxidase family of proteins recently identified in the cochlea, inhibition of which decreased kidney injury molecule-1 expression. Polymerase chain reaction performed on different regions of the cochlea indicated the presence of kidney injury molecule-1 mRNA in the lateral wall, organ of Corti and spiral ganglion. This distribution was confirmed by immunocytochemistry. Taken together, these data identify kidney injury molecule-1 as a novel cochlear injury molecule, whose expression is regulated by reactive oxygen species generated via the NADPH oxidase pathway.
顺铂是一种广泛使用的化疗药物，其剂量限制性副作用包括耳毒性和肾毒性。最近的证据表明，顺铂可诱导一种新蛋白——肾损伤分子-1在肾近端小管上皮细胞中表达，以帮助再生。在本研究中，我们确定肾损伤分子-1是否在内耳中表达以及是否由顺铂诱导表达。利用逆转录聚合酶链反应技术，我们现已在大鼠内耳以及三种不同的小鼠转化毛细胞系中鉴定出肾损伤分子-1。给大鼠注射顺铂会导致听力损失，并诱导大鼠内耳中肾损伤分子-1 mRNA的表达。用硫辛酸（一种活性氧清除剂）对大鼠进行预处理，可显著降低顺铂诱导的听力损失和肾损伤分子-1的表达。顺铂还会增加内耳NOX3 mRNA的表达，NOX3是最近在内耳中发现的超氧化物生成NADPH氧化酶家族蛋白的成员之一，抑制其表达可降低肾损伤分子-1的表达。对耳蜗不同区域进行的聚合酶链反应表明，侧壁、柯蒂氏器和螺旋神经节中存在肾损伤分子-1 mRNA。免疫细胞化学证实了这种分布。综上所述，这些数据确定肾损伤分子-1是一种新的内耳损伤分子，其表达受通过NADPH氧化酶途径产生的活性氧调节。
