Toxicology Letters 176 (2008) 48–57 Available online at www.sciencedirect.com Selective iNOS inhibition reduces renal damage induced by cisplatin Yolanda I. Chirino a , Joyce Trujillo b,c , Dolores Javier S´ anchez-Gonz´ alez d , Claudia Mar´ıa Mart´ınez-Mart´ınez d , Cristino Cruz c , Norma A. Bobadilla b,c , Jos´ e Pedraza-Chaverri a,∗ a Facultad de Qu´ımica, Departamento de Biolog´ıa, Universidad Nacional Aut´ onoma de M´ exico, Mexico b Unidad de Fisiolog´ıa Molecular, Instituto de Investigaciones Biom´ edicas, Universidad Nacional Aut´ onoma de M´ exico, Mexico c Departamento de Nefrolog´ıa, Instituto Nacional de Ciencias M´ edicas y Nutrici ´ on Salvador Zubir ´ an, Mexico d Departamento de Biolog´ıa Celular, Escuela M´ edico Militar, Universidad del Ej´ ercito y Fuerza A´ erea, Mexico Received 7 September 2007; received in revised form 17 October 2007; accepted 17 October 2007 Available online 24 October 2007 Abstract Cisplatin is a chemotherapeutic agent used in the treatment of several cancer tumors; however, nephrotoxicity has restricted its use. Reactive oxygen species and peroxynitrite, which is formed by the reaction between superoxide anion and nitric oxide (NO • ), are implicated in cisplatin-induced nephrotoxicity. In contrast, both toxic and beneficial effects of NO • have been suggested in cisplatin-induced nephrotoxicity. Therefore, nowadays the role of NO • in this experimental model remains controversial. The aim of the present work was to elucidate the role of NO • in cisplatin-induced renal damage using N-[3-(aminomethyl)benzyl]acetamidine (1400W), a selective and irreversible inhibitor of iNOS. The mRNA levels of iNOS were increased in cisplatin-treated rats. The administration of 1400W reduced the cisplatin induced histological damage, renal dysfunction (increase in proteinuria and kidney injury molecule expression and decrease in creatinine clearance), tubulointerstitial infiltration, oxidative stress (increase in renal malondialdehyde and inmmunostaining for 4-hydroxy-2-nonenal) and nitrosative stress (immunostaining for 3-nitrotyrosine). In addition, the administration of 1400W was unable to modify systolic blood pressure in control rats. Our data demonstrate that selective iNOS inhibition reduces the cisplatin-induced nephrotoxicity and nitrosative stress which strongly suggest that in this experimental model (1) the NO • production is toxic and (2) iNOS is the main source of NO • . © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Cisplatin; 1400W; Inducible nitric oxide synthase (iNOS); Nitric oxide (NO • ) 1. Introduction Cisplatin (Cis-diamminedichloroplatinum II) is a chemotherapeutic agent useful in the treatment of tes- ∗ Corresponding author. Facultad de Qu´ımica, Departamento de Biolog´ıa, Edificio F, Segundo Piso, Laboratorio 209, Universidad Nacional Aut´ onoma de M´ exico (UNAM), Ciudad Universitaria, 04510, M´ exico, D.F., Mexico. Tel.: +52 55 5622 3878; fax: +52 55 5622 3878. E-mail address: pedraza@servidor.unam.mx (J. Pedraza-Chaverri). ticular, ovarian, bladder, breast, head, and neck cancers (Lebwohl and Canetta, 1998). Nephrotoxicity, how- ever, is the dose-limiting factor for cisplatin clinical use (Daugaard and Abildgaard, 1989). Cellular and molecular mechanisms responsible for cisplatin-induced nephrotoxicity are not well understood, but there is evidence that the formation of reactive species is involved in producing renal damage. Role of oxida- tive and nitrosative stress is additionally supported by the protective effect of several free radical scavengers and antioxidants (Chirino et al., 2004; Masuda et al., 1994; Nishikawa et al., 2001; Tsuruya et al., 2003; 0378-4274/$ – see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.toxlet.2007.10.006