title: P2X7 receptor blockade protects against cisplatin-induced nephrotoxicity in mice by decreasing the activities of inflammasome components, oxidative stress and caspase-3.
abstract: Nephrotoxicity is a common complication of cisplatin chemotherapy and thus limits the use of cisplatin in clinic. The purinergic 2X7 receptor (P2X7R) plays important roles in inflammation and apoptosis in some inflammatory diseases; however, its roles in cisplatin-induced nephrotoxicity remain unclear. In this study, we first assessed the expression of P2X7R in cisplatin-induced nephrotoxicity in C57BL/6 mice, and then we investigated the changes of renal function, histological injury, inflammatory response, and apoptosis in renal tissues after P2X7R blockade in vivo using an antagonist A-438079. Moreover, we measured the changes of nod-like receptor family, pyrin domain containing proteins (NLRP3) inflammasome components, oxidative stress, and proapoptotic genes in renal tissues in cisplatin-induced nephrotoxicity after treatment with A-438079. We found that the expression of P2X7R was significantly upregulated in the renal tubular epithelial cells in cisplatin-induced nephrotoxicity compared with that of the normal control group. Furthermore, pretreatment with A-438079 markedly attenuated the cisplatin-induced renal injury while lightening the histological damage, inflammatory response and apoptosis in renal tissue, and improved the renal function. These effects were associated with the significantly reduced levels of NLRP3 inflammasome components, oxidative stress, p53 and caspase-3 in renal tissues in cisplatin-induced nephrotoxicity. In conclusions, our studies suggest that the upregulated activity of P2X7R might play important roles in the development of cisplatin-induced nephrotoxicity, and P2X7R blockade might become an effective therapeutic strategy for this disease.
authors.affiliation: Department of Nephrology, Xinqiao Hospital, PLA, Third Military Medical University, Chongqing 400037, PR China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Nephrology, Xinqiao Hospital, PLA, Third Military Medical University, Chongqing 400037, PR China.
authors.forename: Fahuan
authors.initials: F
authors.lastname: Yuan
authors.affiliation: Department of Nephrology, Xinqiao Hospital, PLA, Third Military Medical University, Chongqing 400037, PR China.
authors.forename: Xuejiao
authors.initials: X
authors.lastname: Cao
authors.affiliation: Department of Dermatology, Southwest Hospital, Third Military Medical University, Chongqing 400038, PR China.
authors.forename: Zhifang
authors.initials: Z
authors.lastname: Zhai
authors.affiliation: Department of Medical Genetics, Third Military Medical University, Chongqing 430038, PR China.
authors.lastname: GangHuang
authors.affiliation: Department of Nephrology, Xinqiao Hospital, PLA, Third Military Medical University, Chongqing 400037, PR China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Du
authors.affiliation: Department of Nephrology, Xinqiao Hospital, PLA, Third Military Medical University, Chongqing 400037, PR China.
authors.forename: Yiqin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Nephrology, Xinqiao Hospital, PLA, Third Military Medical University, Chongqing 400037, PR China.
authors.forename: Jingbo
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Nephrology, Xinqiao Hospital, PLA, Third Military Medical University, Chongqing 400037, PR China.
authors.forename: Yunjian
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Nephrology, Xinqiao Hospital, PLA, Third Military Medical University, Chongqing 400037, PR China.
authors.forename: Jinghong
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Nephrology, Xinqiao Hospital, PLA, Third Military Medical University, Chongqing 400037, PR China. Electronic address: hwp0518@aliyun.com.
authors.forename: Weiping
authors.initials: W
authors.lastname: Hou
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism*; D002945:Cisplatin / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D058847:Inflammasomes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C523668:3-(5-(2,3-dichlorophenyl)-1H-tetrazol-1-yl)methylpyridine; D058847:Inflammasomes; D058920:Purinergic P2X Receptor Antagonists; D011725:Pyridines; D058486:Receptors, Purinergic P2X7; D013777:Tetrazoles; D053148:Caspase 3; D002945:Cisplatin
keywords: Apoptosis; Caspase-3; Cisplatin-induced nephrotoxicity; NLRP3 inflammasome; Oxidative stress; P2X7R