Renal injury by cisplatin has been associated with oxidative

Renal injury by cisplatin has been associated with oxidative stress, inflammation, and apoptosis (Francescato et al., 2007, Iseri et al., 2007, Kiymaz et al., 2008, Ueki et al., 2012). Specifically, apoptosis is an important mode of cell death in cisplatin nephrotoxicity, and many studies including ours have demonstrated renal tubular cell apoptosis after cisplatin treatment. The binding of extracellular TNF-α to a cell surface receptor activates caspase 8, upregulates the pro-apoptotic protein Bax, and downregulates the anti-apoptotic protein Bcl-2 (Sahu et al., 2013, Tsuruya et al., 2003, Ueki et al., 2012). Caspase activation is thought to be important in the genesis of apoptosis. In particular, caspase-3, the execution caspase, is instrumental in the apoptotic process; it cleaves and activates poly (ADP-ribose) polymerase which leads to DNA fragmentation (Lau, 1999, Lieberthal et al., 1996). ET-1 directly inhibits Na-K-ATPase of renal tubular ITD 1 australia Garvin and Sanders (1991) and modulates a variety of signal transduction pathways through its receptors as well. Therefore, while there is little doubt that ET-1 plays a certain role in the pathogenesis of renal diseases, it is not yet clear whether ET-1 acts as a causative factor in various renal diseases including ARF. Lee and Ahn (2008) demonstrated increased ET-1 peptide and ET-1 mRNA in cisplatin-treated mice. Although ET-1 exerts its action through ETA and/or ETB, expression of ET receptors varies depending on ARF models used. Lee and Ahn (2008) showed that the expressions of ET-1 and ETA receptors, but not ETB, were increased, suggesting that the individual components of the renal ET system are differentially regulated in cisplatin-induced nephrotoxic ARF. Therefore, drug targeting to ETA receptor could help lessen nephrotoxic ARF induced by cisplatin. The reno-protective effect of the ETA selective antagonist BQ-123 has been documented against other nephrotoxic drugs as cyclosporine A (Kivlighn et al., 1994) as well as against ischemia-induced ARF (Erdogan et al., 2006). Concurrent administration of BQ-123 with cisplatin resulted in significant reduction in serum blood urea nitrogen and creatinine levels compared to rats treated with cisplatin alone. This was supported by the histological sections showing normal morphology. Up to our knowledge, this study is the first to reveal that selective ETA receptor blockade could significantly attenuate cisplatin-induced nephrotoxicity. It could be concluded that ET-1-induced vasoconstriction via ETA may contribute significantly but not completely to cisplatin-induced nephrotoxicity; BQ-123 targets only one of the pathophysiologic pathways for cisplatin which is the haemodynamic tone. In addition, increased expression of both ET-1 and ETA receptors in mice shown previously by Lee and Ahn (2008) was not an adaptive defensive reaction against cisplatin pathophysiological effects; but rather contributed to the cisplatin-induced nephrotoxicity. Furthermore, the current study is the first to give evidence that the ETA receptor selective antagonist BQ-123 reverses the cisplatin-induced ARF and that this effect requires the presence of an intact SOD enzymatic activity and functional ETB receptors. A notion that could be evidenced by the results obtained from the concurrent administration of the non-selective ET-1 blocker bosentan with cisplatin, which failed to reverse the cisplatin-induced ARF manifested as increases in blood urea nitrogen and serum creatinine. Despite the fact that its co-administration was able to reverse cisplatin-induced changes in MDA, NO, TNF-α and caspase-3. Furthermore, the contradictory results obtained from the two blockers used highlighted the importance of presence of functional ETB receptors to elucidate the protective effect of BQ-123 against cisplatin-induced ARF; since the blockade of ETB receptors mediated vasorelaxation (Mazzuca et al., 2013) seems to nullify the expected beneficial effects of the simultaneous blockade of ETA receptors mediated vasoconstriction during cisplatin-induced acute renal damage.