Salicylate reduces cisplatin nephrotoxicity by inhibition of tumor necrosis factor-α

Ganesan Ramesh, W. Brian Reeves

Research output: Contribution to journalArticlepeer-review

113 Scopus citations


Background. Salicylate was recently shown to provide protection against cisplatin nephrotoxicity in rats. We have demonstrated that enhanced tumor necrosis factor-α (TNF-α) production mediates, in part, cisplatin nephrotoxicity. The purpose of this study was to determine if the protective effects of salicylate were mediated through inhibition of TNF-α in vivo and to explore the mechanism of inhibition in vitro. Methods. The effects of treatment with cisplatin alone and in combination with sodium salicylate in mice on renal function, histology, and gene expression were determined. The effects of cisplatin and salicylate on TNF-α expression, nuclear factor kappa B (NF-κB) activity, and apoptosis were determined in vitro using cultured murine proximal tubule cells. Results. Salicylate significantly reduced both the functional and histologic evidence of cisplatin renal injury. Cisplatin increased the renal expression of TNF-α, monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule (ICAM)-1, heme oxygenase-1, TNF receptor 1 (TNFR1), and TNF receptor 2 (TNFR2). Treatment with sodium salicylate blunted the increase in TNF-α mRNA and also reduced serum TNF-α protein levels. Salicylate had little protective effect when administered with cisplatin to TNF-α-deficient mice. Cisplatin increased the degradation of I kappa B (IκB) in a time-dependent manner and also increased nuclear NF-κB binding activity. Salicylate inhibited IκB degradation and NF-κB binding activity in the presence of cisplatin. In addition, salicylate inhibited the cisplatin induced TNF-α mRNA increase in mouse proximal tubule epithelial (TKPT) cells. Conclusion. These results indicate that salicylate acts via inhibition of TNF-α production to reduce cisplatin nephrotoxicity. The inhibition of TNF-α production may be mediated via stabilization of IκB.

Original languageEnglish (US)
Pages (from-to)490-498
Number of pages9
JournalKidney international
Issue number2
StatePublished - Feb 2004
Externally publishedYes


  • Acute tubular necrosis
  • Cytokines
  • Gene expression
  • IκB
  • NF-κB
  • Tumor necrosis factor receptor

ASJC Scopus subject areas

  • Nephrology


Dive into the research topics of 'Salicylate reduces cisplatin nephrotoxicity by inhibition of tumor necrosis factor-α'. Together they form a unique fingerprint.

Cite this