Cysteinyl leukotriene receptor antagonism alleviates renal injury induced by ischemia-reperfusion in rats

Abstract

BackgroundRenal inflammation has an important role in the development of ischemia-reperfusion injury of the kidney. Cysteinyl leukotrienes have been implicated in many inflammatory conditions. The aim of this study was to investigate the ability of the cysteinyl leukotriene receptor blocker, zafirlukast, to alleviate renal dysfunction and injury in a rat model of renal ischemia-reperfusion injury. MethodsWe induced renal ischemia for 45 min, followed by 24 h reperfusion. We gave zafirlukast at a dose of 20 mg/kg/d for 3 d before ischemia-reperfusion. At the end of the reperfusion (24 h), we collected blood samples to measure blood urea nitrogen, creatinine, tumor necrosis factor-α, intercellular adhesion molecule-1, and nitrite/nitrate. We took kidney samples for histological and immunohistochemical assessment, and to measure malondialdehyde, glutathione content, and myeloperoxidase activity. ResultsInduction of renal ischemia-reperfusion resulted into renal dysfunction, as indicated by elevated levels of blood urea nitrogen and serum creatinine, serum nitrite and nitrate, serum tumor necrosis factor-α, and intercellular adhesion molecule-1. An oxidative stress marker, renal malondialdehyde concentration, was increased, whereas renal reduced glutathione content was decreased. Myeloperoxidase activity, suggestive of neutrophil infiltration, was elevated in renal tissues. Histological changes confirmed these biochemical changes, as did P-selectin overexpression in renal tissues subjected to ischemia-reperfusion. Administration of zafirlukast before ischemia-reperfusion improved renal functions and reduced serum levels of nitrite and nitrate, tumor necrosis factor-α, and intercellular adhesion molecule-1, renal concentration of myeloperoxidase activity, and malondialdehyde concentration, whereas increased renal reduced glutathione concentration. Moreover, zafirlukast reduced histopathological features of tubular injury and P-selectin overexpression in both cortex and medulla. ConclusionsThese results demonstrate that zafirlukast significantly reduces the severity of ischemic acute renal failure, probably via anti-inflammatory action, reduction of neutrophil infiltration into renal tissues, and oxidative stress subsequent to an attenuation of P-selectin expression.