Endotoxin and cisplatin synergistically induce renal dysfunction and cytokine production in mice.
A major toxicity of the cancer chemotherapeutic agent cisplatin is acute renal failure. Sepsis is a common cause of acute renal failure in humans and patients who receive cisplatin are at increased risk for sepsis. Accordingly, this study examined the interactions between cisplatin and endotoxin in vivo with respect to renal function and cytokine production. Mice were treated with either a single dose of cisplatin or two doses of LPS administered 24 h apart, or both agents in combination. Administration of 10 mg/kg cisplatin had no effect on blood urea nitrogen or creatinine levels throughout the course of the study. LPS resulted in a modest rise in blood urea nitrogen at 24 and 48 h, which returned to normal by 72 h. In contrast, mice treated with both cisplatin and LPS developed severe renal failure and an increase in mortality. Urine, but not serum, TNF-alpha levels showed a synergistic increase by cisplatin and LPS. Urinary IL-6, MCP-1, KC, and GM-CSF also showed a synergistic increase with cisplatin+LPS treatment. The renal dysfunction induced by cisplatin+LPS was completely dependent on TLR4 signaling and partially dependent on TNF-alpha production. Increased cytokine production was associated with a moderate increase in infiltrating leukocytes which was not different between cisplatin+LPS and LPS alone. These results indicate that cisplatin and LPS act synergistically to produce nephrotoxicity which may involve proinflammatory cytokine production.
Ramesh
Ganesan
G
Division of Nephrology, Pennsylvania State College of Medicine, 500 Univ. Dr., Hershey, PA 17033, USA.
Zhang
Binzhi
B
Uematsu
Satoshi
S
Akira
Shizuo
S
Reeves
W Brian
WB
D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001806:Blood Urea Nitrogen; D018925:Chemokines / Q000096:biosynthesis; D002945:Cisplatin / Q000633:toxicity*; D003404:Creatinine / Q000097:blood; D016207:Cytokines / Q000096:biosynthesis*; D004731:Endotoxins / Q000633:toxicity*; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007677:Kidney Function Tests; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000187:drug effects / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000652:urine
D000970:Antineoplastic Agents; D018925:Chemokines; D016207:Cytokines; D004731:Endotoxins; D012333:RNA, Messenger; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D003404:Creatinine; D002945:Cisplatin