TLR4 receptor blockade diminishes cardiac and renal toxicity induced by cisplatin treatment in rats

Abstract

Background: Cisplatin's use is limited by renal and cardiovascular toxicity, among others. This toxicity is mediated, in part, by the capacity of cisplatin to activate TLR4/MyD88/NLRP3 signaling cascade, leading to sterile inflammation. The aim of the present study is to evaluate whether blockade of TLR4 receptors can ameliorate cardio-renal toxicity induced by cisplatin, analyzing the modulation of oxidative stress and/or inflammatory pathways. Methods: Adult male Wistar rats were divided into three treatment groups: saline, cisplatin 3 mg/kg, cisplatin 3 mg/kg + TLR4 blocker (TLR4-ANT) 10 mg/kg. Saline and cisplatin were administered intraperitoneally once a week for five experimental weeks. TLR4-ANT was administered intraperitoneally once a day, for the last two experimental weeks. Blood pressure, heart rate, basal cardiac function, contractile vascular reactivity and renal function were evaluated. Malondialdehyde (MDA) levels and TLR4/MyD88/NLRP3 axis protein and IL-18 level expressions, in target tissues, have also been assessed. Results: TLR4 antagonist treatment prevented cardiovascular and renal alterations in cisplatin-treated animals. TLR4 antagonist modulated the TLR4/MyD88/NLRP3 axis to exert its effects, particularly in the kidney. It produced a modest reduction in cisplatin-induced upregulation of NLRP3 in the heart and in TLR4 and NLRP3 expression in the kidney. In parallel, TLR4 antagonist caused a slight decrease in renal IL-18 expression and decoupled the relationship between NLRP3 and IL-18 expression. Conclusion: TLR4 receptor blockade could be a strategy to mitigate the inflammatory pathways involved in both cardiovascular and renal toxicity, caused by cisplatin cycle treatment.