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  • Interestingly increased level of both circulating ET and uri

    2021-07-23

    Interestingly, increased level of both circulating ET-1 and urinary excretion of ET-1 have been observed in patients treated with nephrotoxic immunosuppressive agents as cyclosporine A and tacrolimus (Slowinski et al., 2002). Other nephrotoxic agents, such as cisplatin, also increase urinary excretion of ET. Moreover, expressions of ET-1 have been found to be elevated in mice with cisplatin-induced acute renal failure (ARF), suggesting that ET-1 might play a role in the pathogenesis of such a disease (Lee and Ahn, 2008). ET receptor antagonism improved renal failure after ARF (Gellai et al., 1994). Treatment with an ETA receptor antagonist before or post-ischemia has been demonstrated to lessen glomerular dysfunction in rats (Wilhelm et al., 2001). Buyukgebiz et al. (1996) mentioned that inhibiting function of ET via an ETA receptor antagonist might prevent reperfusion injury in kidney transplantation. Bosentan is a non-selective endothelin receptors antagonist that blocks both ETA and ETB. In contrast, BQ-123 2-[(3R,6R,9S,12R,15S)-6-(1H-indol-3-ylmethyl)-9-(2-methylpropyl)-2,5,8,11,14-pentaoxo-12-propan-2-yl-1,4,7,10,13-pentazabicyclo[13.3.0]octadecan-3-yl]acetic Triflusal mg is an ETA receptor selective antagonist (Buyukgebiz et al., 1996). In clinical trials, bosentan and other non-selective antagonists as well as ETA receptor selective antagonists have produced beneficial effects on hemodynamics and other symptoms in heart failure, pulmonary hypertension, and essential hypertension (Wilhelm et al., 2001). Therefore, the current study aimed at investigating the possibility that inhibiting the physiological function of ET-1 by blocking its receptors would significantly decrease the nephrotoxic effect of cisplatin. We, therefore, evaluated the reno-protective effects of both the non-selective ET receptors antagonist bosentan and the ETA receptor selective antagonist BQ-123 against cisplatin-induced nephrotoxicity.
    Materials and methods
    Results
    Discussion There are few reports on the expression of the ET system in nephrotoxic ARF. In cisplatin-induced nephrotoxic ARF, previous reports demonstrated that renal damages were confined to the cortex, and that ET-1 and ETA receptors were up-regulated without change of ETB receptors (Lee and Ahn, 2008). However, the current study is the first to report the protective effect of the selective ETA receptor blocker, BQ-123, against cisplatin-induced ARF. Results of the current study demonstrated that acute administration of cisplatin (6mg/kg) to male rats led to histological alterations of the renal tubular cells. These changes were associated with decline in renal functions, leading to increased concentrations of serum creatinine and blood urea nitrogen, and are in line with previous studies (Evenepoel, 2004, Lameire et al., 2005, Sahu et al., 2013). Furthermore, the findings of the current study point to the presence of oxidative stress and are in accordance with data in previous reports (Antunes et al., 2001, Mora et al., 2003, Sahu et al., 2013, Weijl et al., 1997). Despite the fact that the underlying mechanism of cisplatin-induced nephrotoxicity is still unclear, in vitro and in vivo studies provide strong evidence that implicate oxidative stress as a mediator of cisplatin-induced nephrotoxicity (Baliga et al., 1998, Kuhlmann et al., 1997, Sahu et al., 2013). Cisplatin was found to generate superoxide and hydroxyl radicals, and to stimulate renal lipid peroxidation (Kuhlmann et al., 1997). As a result, an imbalance between generation of oxygen-derived radicals and endogenous enzymatic and non-enzymatic antioxidants will occur leading to oxidative damage of cell components (Weijl et al., 1997). The role of NO in cisplatin nephrotoxicity is unclear. Previous studies had shown a decreased NO level measured as total nitrate/nitrite level following cisplatin administration (Saad et al., 2002, Saleh and El-Demerdash, 2005), which is in line with results of the current study. The decrease in NO synthesis induced by cisplatin can be explained by the detected pathological damage of glomerular endothelial cells. Previous studies suggested that changes in renal haemodynamics play an important role in cisplatin-induced nephrotoxicity.