Cysteinyl leukotrienes predominantly mediate cisplatin-induced acute renal damage in male rats

Previous studies, including ours, demonstrated that activation of 5-lipoxygenase pathway and its products play a role in mediating cisplatin nephrotoxicity. Here, we tested the hypothesis whether these products, namely cysteinyl (Cys-LTs) and non cyseinyl leukotrienes (non Cys-LTs), would differentially contribute to cisplatin-induced acute renal damage in rats. Male Sprague-Dawley rats were treated with a single intraperitoneal dose of cisplatin (5 mg/kg) alone or combined with montelukast (Cys-LT receptor blocker, 10 mg/kg/day, orally), or ONO-4057 (leukotriene B₄ receptor blocker, 300 mg/kg/day, orally). Both drugs were administered for one week; starting 4 days before cisplatin injection. Cisplatin nephrotoxicity was evidenced by alteration in renal indices of functional (blood urea nitrogen, and serum creatinine), oxidative (increased thiobarbituric acid reactive substances, nitrite/nitrate level and decreased total superoxide dismutase activity), inflammatory (increased tumor necrosis factor-α and myeloperoxidase), anti-inflammatory (interleukin-10), apoptotic (caspase-3), fibrotic (transforming growth factor-β1), and histopathological profiles. These changes were accompanied by increased renal levels of Cys (leukotriene D₄, 3.9-folds) and non Cys-LTs (leukotriene B₄, 1.3-folds). Simultaneous administration of montelukast, but not ONO-4057, to cisplatin-treated rats reversed the nephrotoxic manifestations, even though in the presence of elevated renal leukotriene B₄. These data suggest, for the first time, the predominant role of Cys-LTs in mediating cisplatin-induced acute renal damage in rats.