Expression of the kidney injury molecule 1 in the rat cochlea and induction by cisplatin.
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.
Mukherjea
D
D
Department of Pharmacology, Southern Illinois University School of Medicine, PO Box 19629, Springfield, IL 62794-9626, USA.
Whitworth
C A
CA
Nandish
S
S
Dunaway
G A
GA
Rybak
L P
LP
Ramkumar
V
V
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000627:therapeutic use; D015152:Blotting, Northern / Q000379:methods; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002945:Cisplatin / Q000494:pharmacology*; D003051:Cochlea / Q000187:drug effects*; D004347:Drug Interactions; D015870:Gene Expression / Q000187:drug effects*; D034381:Hearing Loss / Q000188:drug therapy / Q000503:physiopathology; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D008063:Thioctic Acid / Q000627:therapeutic use; D013997:Time Factors
D000970:Antineoplastic Agents; D000975:Antioxidants; D015815:Cell Adhesion Molecules; D002945:Cisplatin; D008565:Membrane Proteins; D012333:RNA, Messenger; D008063:Thioctic Acid; C110936:Havcr1 protein, rat