Pyrrolidine dithiocarbamate reduces renal dysfunction and injury caused by ischemia/reperfusion of the rat kidney Prabal K. Chatterjee a,1 , Roberta D’Emmanuele di Villa Bianca b , Ahila Sivarajah a , Michelle C. McDonald a , Salvatore Cuzzocrea c , Christoph Thiemermann a, * a Department of Experimental Medicine, Nephrology and Critical Care, William Harvey Research Institute, Queen Mary, University of London, Charterhouse Square, London EC1M 6BQ, UK b Department of Experimental Pharmacology, University of Naples, Naples, Italy c Department of Clinical and Experimental Medicine and Pharmacology, Institute of Pharmacology, School of Medicine, University of Messina, Messina, Italy Received 17 September 2003; accepted 23 September 2003 Abstract Dithiocarbamates can modulate the expression of genes associated with inflammation or development of ischemia/reperfusion injury. Here, we investigate the effects of pyrrolidine dithiocarbamate, an inhibitor of nuclear factor (NF)-nB activation, on the renal dysfunction and injury caused by ischemia/reperfusion of the rat kidney. Bilateral clamping of renal pedicles (45 min) followed by reperfusion (6 h) caused significant renal dysfunction and marked renal injury. Pyrrolidine dithiocarbamate (100 mg/kg, administered i.v.) significantly reduced biochemical and histological evidence of renal dysfunction and injury caused by ischemia/reperfusion of the rat kidney. Furthermore, pyrrolidine dithiocarbamate markedly reduced the expression of inducible nitric oxide synthase (iNOS) protein and significantly reduced serum levels of nitric oxide. Finally, pyrrolidine dithiocarbamate inhibited the activation of NF-nB by preventing its translocation from the cytoplasm into the nuclei of renal cells. These results demonstrate that pyrrolidine dithiocarbamate reduces renal ischemia/reperfusion injury and that dithiocarbamates may provide beneficial actions against ischemic acute renal failure. D 2003 Elsevier B.V. All rights reserved. Keywords: Renal/kidney; Reperfusion-injury; Dithiocarbamates; Pyrrolidine dithiocarbamate; Nuclear factor-nB; Inducible nitric oxide synthase; Nitric oxide 1. Introduction Despite significant advances in critical care medicine, acute renal failure remains a major clinical problem, causing considerable morbidity and mortality that has not decreased significantly over the last 50 years (Lameire and Vanholder, 2001). Previous interventions against acute renal failure have proved to be largely negative and dialysis still remains the only effective therapy (Star, 1998). Thus, the development of novel therapeutic interventions against acute renal failure has remained a topic of intense research interest (Star, 1998; Lameire and Vanholder, 2001). Renal ischemia initiates a complex and interrelated sequence of events, resulting in the injury and death of renal cells (Lieberthal and Levine, 1996; Thadhani et al., 1996). Reperfusion, although essential for the survival of ischemic renal tissue, causes additional damage (reperfusion injury) (Paller, 1994a; Weight et al., 1996). Together, ischemia/reperfusion of the kidney contribute to the renal dysfunction and injury associated with ischemic acute renal failure (Thadhani et al., 1996; Weight et al., 1996). The transcription factor nuclear factor (NF)-nB, a hetero- trimeric complex composed of p50, p65 (Rel A) and inhib- itor (I)nB-a (InB-a) (Boone et al., 2002; Sun and Andersson, 2002), plays a pivotal role in the expression of numerous genes and mediators involved in normal and pathophysio- logical processes including inducible nitric oxide synthase (iNOS), cyclooxygenase-2, adhesion molecules and numer- ous cytokines and chemokines (Xie et al., 1994; Baeuerle and Baichwal, 1997; Barnes and Karin, 1997; Sun and Andersson, 2002). The expression of several of these genes and mediators has been implicated in the pathophysiology of renal disease and development of acute renal failure, indi- cating an important role for NF-nB activation (Guijarro and Egido, 2001; Wardle, 2001). 0014-2999/$ - see front matter D 2003 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2003.09.071 * Corresponding author. Tel.: +44-20-7882-6025; fax: +44-20-7251- 1685. E-mail address: c.thiemermann@qmul.ac.uk (C. Thiemermann). 1 Current address: Department of Pharmacology, School of Pharmacy and Biomolecular Sciences, University of Brighton, Cockcroft Building, Moulsecoomb, Brighton BN2 4GJ, UK. www.elsevier.com/locate/ejphar European Journal of Pharmacology 482 (2003) 271 – 280