The leukotriene B4-leukotriene B4receptor 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 B4receptor 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 LTB4synthesis and BLT1 expression in the kidney after cisplatin administration. Cisplatin was found to directly upregulate gene expression of leukotriene A4hydrolase and stimulate LTB4production 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.
Division of Nephrology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
Bo
B
Deng
Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Yuli
Y
Lin
Division of Nephrology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
Shuai
S
Ma
Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, China.
Yin
Y
Zheng
Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
Xuguang
X
Yang
Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Bingji
B
Li
Division of Nephrology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
Wenyan
W
Yu
Division of Nephrology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
Qingqing
Q
Xu
Division of Nephrology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
Tingyan
T
Liu
Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, China.
Chuanming
C
Hao
Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China. Electronic address: ruihe@fudan.edu.cn.
Rui
R
He
Division of Nephrology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China. Electronic address: dingfeng@sjtu.edu.cn.
Feng
F
Ding
D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D002945:Cisplatin; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020024:Leukotriene Antagonists / Q000494:pharmacology; D007975:Leukotriene B4 / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation; D010641:Phenotype; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors
D004791:Enzyme Inhibitors; D020024:Leukotriene Antagonists; C503704:Ltb4r1 protein, mouse; D018102:Receptors, Leukotriene B4; D007975:Leukotriene B4; D004851:Epoxide Hydrolases; D002945:Cisplatin; C043134:leukotriene A4 hydrolase
acute kidney injury; cisplatin nephrotoxicity; leukotriene B(4); leukotriene B(4) receptor 1; neutrophils