title: Dendritic Cell Protection from Cisplatin Nephrotoxicity Is Independent of Neutrophils.
abstract: Cisplatin is a very effective chemotherapeutic agent used against a wide range of solid tumors. A major adverse effect of cisplatin therapy is acute kidney injury (AKI). Neutrophils are reported to infiltrate and exacerbate injury in a wide range of sterile inflammatory models of tissue injury. Here, we studied the kinetics of neutrophil infiltration into kidneys and their role in cisplatin-mediated AKI. Mice treated with cisplatin showed an increase in circulating neutrophils 24 and 48 h after cisplatin administration. Cisplatin treatment caused an increase in kidney leukocytes with neutrophils accounting for the majority of the infiltrating leukocytes. The extent of neutrophil infiltration coincided with the severity of kidney injury and renal dysfunction. To examine the functional relevance of infiltrating neutrophils in cisplatin nephrotoxicity, we depleted neutrophils using a neutrophil-specific antibody (anti-Ly-6G). This antibody resulted in greater than 90% depletion of neutrophils in both the blood and kidney. Of note, depletion of neutrophils had no impact on the extent of cisplatin-induced AKI as compared to non-depleted mice. Earlier, we reported that dendritic cell depletion in CD11c-DTRtg mice causes exacerbation of AKI and a dramatic increase in renal neutrophils. Thus, we also examined the role of neutrophils in dendritic cell-depleted mice treated with cisplatin. Dendritic cell depletion exacerbated AKI in spite of neutrophil depletion. These data demonstrate that cisplatin nephrotoxicity is not mediated by neutrophils and that dendritic cells protect kidneys via neutrophil-independent mechanisms.
authors: Division of Nephrology, the Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
authors: Raghu K
authors: RK
authors: Tadagavadi
authors: Division of Nephrology, the Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA. guofgao@gmail.com.
authors: Guofeng
authors: G
authors: Gao
authors: Division of Nephrology, the Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA. www2@psu.edu.
authors: Wei Wei
authors: WW
authors: Wang
authors: Division of Nephrology, the Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA. noli_rovira@hotmail.com.
authors: Manuel Rovira
authors: MR
authors: Gonzalez
authors: Division of Nephrology, the Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA. wreeves@psu.edu.
authors: W Brian
authors: WB
authors: Reeves
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000276:immunology*; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002945:Cisplatin / Q000633:toxicity*; D019610:Cytoprotection; D003713:Dendritic Cells / Q000276:immunology*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009504:Neutrophils / Q000276:immunology
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin
keywords: cisplatin; dendritic cells; kidney injury; nephrotoxicity; neutrophils