Endotoxin and cisplatin synergistically induce renal dysfunction and cytokine production in mice

Ganesan Ramesh, Binzhi Zhang, Satoshi Uematsu, Shizuo Akira, W. Brian Reeves

Research output: Contribution to journalArticle

68 Scopus citations

Abstract

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-α 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-α 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.

Original languageEnglish (US)
Pages (from-to)F325-F332
JournalAmerican Journal of Physiology - Renal Physiology
Volume293
Issue number1
DOIs
StatePublished - Jul 1 2007

    Fingerprint

Keywords

  • Acute renal failure
  • Cytokines
  • Sepsis
  • Toll-like receptor 4
  • Tumor necrosis factor-α

ASJC Scopus subject areas

  • Physiology
  • Urology

Cite this