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

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.