IL-1 receptor blockade alleviates endotoxin-mediated impairment of renaldrug excretory functions in rats

摘要

The aim of ourstudy was to investigate whether two potent anti-inflammatory agents,dexamethasone and anakinra, an IL-1 receptor antagonist, may influ-ence acute kidney injury (AKI) and associated drug excretory func-tions during endotoxemia (LPS) in rats. Ten hours after LPS admi-nistration, untreated endotoxemic rats developed typical symptoms ofAKI, with reduced GFR, impaired tubular excretion of urea andsodium, and decreased urinary excretion of azithromycin, an anionicsubstrate for multidrug resistance-transporting proteins. Administra-tion of both immunosuppressants attenuated the inflammatory re-sponse, liver damage, AKI, and increased renal clearance of azithro-mycin mainly by restoration of GFR, without significant influence onits tubular secretion. The lack of such an effect was related to thedifferential effect of both agents on the renal expression of individualdrug transporters. Only dexamethasone increased the urinary clear-ance of bile acids, in accordance with the reduction of the apicaltransporter (Asbt) for their tubular reabsorption. In summary, our datademonstrated the potency of both agents used for the prevention ofAKI, imposed by endotoxins, and for the restoration of renal drugelimination, mainly by the improvement of GFR. The influence ofboth drugs on altered tubular functions and the expression of drugtransporters was differential, emphasizing the necessity of knowledgeof transporting pathways for individual drugs applied during sepsis.The effect of anakinra suggests a significant contribution of IL-1signaling to the pathogenesis of LPS-induced AKI.