The leukotriene B4-leukotriene B4 receptor axis promotes cisplatin-induced acute kidney injury by modulating neutrophil recruitment

Abstract

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 B₄ receptor 1 (BLT1) mediates the majority of physiological effects of leukotriene B₄ (LTB₄), a potent lipid chemoattractant generated at inflammation sites, but the role of the LTB₄-BLT1 axis in cisplatin-induced AKI remains unknown. Here we found upregulated LTB₄ synthesis and BLT1 expression in the kidney after cisplatin administration. Cisplatin was found to directly upregulate gene expression of leukotriene A₄ hydrolase and stimulate LTB₄ 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 LTB₄-BLT1 axis contributes to cisplatin-induced AKI by mediating kidney recruitment of neutrophils, which induce inflammation and apoptosis in the kidney. Hence, the LTB₄-BLT1 axis could be a potential therapeutic target in cisplatin-induced AKI.

Keywords: acute kidney injury; cisplatin nephrotoxicity; leukotriene B(4); leukotriene B(4) receptor 1; neutrophils.