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 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.

Role of Immune Cells in Acute Kidney Injury and Repair

“…However, discordant results led to questioning of the role of neutrophils during early AKI pathogenesis [2]. Recent studies, however, have shown that blocking neutrophil infiltration by inhibition of vascular adhesion protein-1 or leukotriene B4-leukotriene B4 receptor axis had protective effect against ischemia-reperfusion injury (IRI) and cisplatin-induced AKI, respectively [3,4]. …”

Leukotrienes and kidney diseases

“…In one study, cisplatin induced the biosynthesis of LTB 4 and the expression of its BLT1 receptor in the kidney. The BLT1 receptor antagonist U-75302, BLT1 deficiency and the LTA 4 H inhibitor SC-57461A reduced kidney structural and functional damage, inflammation and apoptosis [ 23 ]. It should be noticed, however, that inhibition of LTA 4 H might direct its substrate LTA 4 towards increased biosynthesis of cysteinyl leukotrienes.…”

Targeting Ltb4 –Blt1 – In Diabetic Nephropathy?

“…[3] LTB4 IN KIDNEY INJURY [4] 1) Leukotriene B4 receptor 1 (BLT1) mediates the majority of physiological effects of leukotriene B4 (LTB4), a powerful lipid chemo-attractant produced at inflammation sites, but the role of the LTB4-BLT1 pathway in cisplatin-induced AKI remains unknown. [4] 2) Up-regulated LTB4 production and BLT1 expression in the kidney after cisplatin administration. Cisplatin was found to directly up-regulate gene expression of leukotriene A4 hydrolase and stimulate LTB4 production in renal tubular epithelial cells.…”

“…Reduced kidney structural/functional damage, inflammation, and apoptosis. [4] 3) LTB4-BLT1 pathway contributes to cisplatin-induced AKI by mediating kidney recruitment of neutrophils, which bring inflammation and apoptosis in the kidney.…”

“…[3] Also in kidney injury LTB4-BLT1 expression is increased which suggest LTB4-BLT-1 is present in renal tissue and widely up regulated in kidney injury. [4] Thus LTB4-BLT1 targeting may be handy tool to handle the complication of diabetes especially nephropathy and retinopathy.…”