Cisplatin upregulates mitochondrial nitric oxide synthase and peroxynitrite formation to promote renal injury
Introduction
Cisplatin (cis-dichlorodiamimine-platinum II) is an effective antineoplastic agent used to treat various solid tumors including cancer of the ovary and testis (Ash, 1980). Nevertheless, its clinical utility is limited due to its cytotoxic adverse effects, which include acute renal failure (ARF) (Gonzales-Vitale et al., 1978). The drug's nephrotoxic effect is characterized by histological changes, primarily in the S3 segment of the proximal tubule. Its associated damage is dose-and duration-dependent in both in vitro and in vivo models (Miura et al., 1987, Kruedering et al., 1998). A range of therapeutic approaches have been designed in order to minimize this associated injury in animal experimental models, but few successful maneuvers have been reported in human treatments and little progress has been made regarding the identification of early biomarkers of injury.
The principal mechanisms of the kidney injury have been debated at length. The most widely recognized events are the induction of cell death by apoptosis and cytoskeleton derangement. F-actin damage and cell detachment have been clearly described for other models of renal epithelial cells (Kruedering et al., 1998) in vitro, and cytoskeleton disorganization has also been documented in a range of models (Tulub and Stefanov, 2001, Kopf-Maier and Muhlhausen, 1992).
Attempting to explain the cisplatin-associated induction of apoptosis, various authors have established its interaction with DNA, which produces a complex that inhibits DNA replication and transcription and impairs DNA damage repair (Zhou et al., 2004). Additionally, cisplatin was also found to inhibit protein synthesis (Lau, 1999) and/or induce mitochondrial injury (Kruedering et al., 1998), finally leading to apoptosis.
Recently, a central role of mitochondrial dysfunction has been reported in in vivo experiments attempting to identify the mechanisms underlying cisplatin-induced nephrotoxicity. The authors demonstrated impairment of the mitochondrial function by various parameters related to oxidative stress and the depletion of the mitochondrial antioxidant defense system (Santos et al., 2007). Previously, it was reported that oxidative damage of mitochondria might be the initial event causing cisplatin-induced renal injury (Chang et al., 2002, Li-Ping et al., 2000).
A toxic role for nitric oxide itself or by generation of nitrosative stress has also been described (Wink et al., 1997). Peroxynitrite promotes nitrosative stress and renal injury in cisplatin-treated rats (Chirino et al., 2004).
As regards the different nitric oxide synthase isoforms involved in cisplatin-mediated damage, it has been reported that inhibition of all nitric oxide synthase isoforms by using N (G)-nitro-l-arginine methyl ester (L-NAME) reduced cisplatin nephrotoxicity (Srivastava et al., 1996, Mansour et al., 2002). However, other studies challenge this assumption and suggest that inhibition of nitric oxide synthase aggravates the injury (Saad et al., 2002, Saleh and El-Demerdash, 2005). Recently, Chirino et al. (2008) corroborated findings of Wink et al. (1997) which suggested that inducible nitric oxide synthase may be an endogenous source for nitric oxide synthesis in cisplatin toxicity. Nevertheless, no information is available about other nitric oxide synthases in cisplatin-associated injury. Although many studies have focused on the mitochondria as central key players, none so far have considered the involvement of mitochondrial nitric oxide synthase.
Recently, we identified mitochondrial nitric oxide synthase as one of the major sources of peroxynitrite generation leading to apoptosis promotion in ischemia-reperfusion (I/R) injured kidneys (Viñas et al., 2006).
In view of the above, the purpose of this study was to determine the involvement of renal mitochondrial nitric oxide synthase and peroxynitrite formation in cisplatin-induced nephrotoxicity.
Section snippets
Pharmacological compounds
Cisplatin and peroxynitrite donor 3-morpholinosydnonimine (SIN-1) were purchased from Sigma (Madrid, Spain). Peroxynitrite scavenger 5,10,15,20-tetrakis (N-methyl-4-pyridyl) porphyrinato iron (III) Chloride (FeTMPyP) was provided by Calbiochem (La Jolla, CA) and selective nNOS inhibitor N-omega-propyl-l-Arginine (L-NPA) was obtained from Tocris (Madrid, Spain).
Experimental animals and groups
Male Sprague Dawley rats weighing 250–300 g were purchased from Charles River (France). The experiment was conducted under the
Mitochondrial nNOS upregulation
In a previous study we reported the nature and role of mitochondrial neuronal nitric oxide synthase (nNOS) upregulation in the promotion of kidney injury after I/R insult. Fig. 1A illustrates the mRNA expression of nNOS in the kidney mitochondrial fraction after cisplatin treatment. The results show a clear induction of mRNA transcription of nNOS in the mitochondria of kidneys of animals treated with cisplatin, indicating the involvement of mitochondrial NOS activity in cisplatin-associated
Discussion
The cytotoxic effects of cisplatin and other anti-cancer drugs are well established and have been studied with regard to the development of renal failure in a variety of models (Kruedering et al., 1998, Huang et al., 2001, Hannemann and Baumann, 1990, Natochin et al., 1989, Park et al., 2002). However, the mechanistic insights in kidney failure after exposure remain complicated.
It seems clear that mitochondria are a major target of cisplatin, and are seriously damaged after cisplatin treatment.
Acknowledgments
The authors would like to thank Ma Ángeles Muñoz for excellent technical support. This work was supported by FIS 05/0156 (awarded to AS) and European Project PL 036813 (awarded to GH). Michaela Jung is supported by a grant from IDIBAPS.
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