The leukotriene B-leukotriene B receptor axis promotes cisplatin-induced acute kidney injury by modulating neutrophil recruitment.

Cisplatin is an effective chemotherapeutic agent and widely used in treatment of various solid organ malignancies, including head and neck, ovarian, and testicular cancers. However, the induction of acute kidney injury (AKI) is one of its main side effects. Leukotriene B receptor 1 (BLT1) mediates the majority of physiological effects of leukotriene B (LTB), a potent lipid chemoattractant generated at inflammation sites, but the role of the LTB-BLT1 axis in cisplatin-induced AKI remains unknown. Here we found upregulated LTB synthesis and BLT1 expression in the kidney after cisplatin administration. Cisplatin was found to directly upregulate gene expression of leukotriene A hydrolase and stimulate LTB production in renal tubular epithelial cells. Reduced kidney structural/functional damage, inflammation, and apoptosis were observed in BLT1 mice, as well as in wild-type mice treated with the LTA4H inhibitor SC-57461A and the BLT1 antagonist U-75302. Neutrophils were likely the target of this pathway, as BLT1 absence induced a significant decrease in infiltrating neutrophils in the kidney. Adoptive transfer of neutrophils from wild-type mice restored kidney injury in BLT1 mice following cisplatin challenge. Thus, the LTB-BLT1 axis contributes to cisplatin-induced AKI by mediating kidney recruitment of neutrophils, which induce inflammation and apoptosis in the kidney. Hence, the LTB-BLT1 axis could be a potential therapeutic target in cisplatin-induced AKI.