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

Kidney Int. 2004 Feb;65(2):490-9. doi: 10.1111/j.1523-1755.2004.00413.x.


Background: Salicylate was recently shown to provide protection against cisplatin nephrotoxicity in rats. We have demonstrated that enhanced tumor necrosis factor-alpha (TNF-alpha) 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-alpha 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-alpha expression, nuclear factor kappa B (NF-kappa B) 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-alpha, 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-alpha mRNA and also reduced serum TNF-alpha protein levels. Salicylate had little protective effect when administered with cisplatin to TNF-alpha-deficient mice. Cisplatin increased the degradation of I kappa B (I kappa B) in a time-dependent manner and also increased nuclear NF-kappa B binding activity. Salicylate inhibited I kappa B degradation and NF-kappa B binding activity in the presence of cisplatin. In addition, salicylate inhibited the cisplatin induced TNF-alpha mRNA increase in mouse proximal tubule epithelial (TKPT) cells.

Conclusion: These results indicate that salicylate acts via inhibition of TNF-alpha production to reduce cisplatin nephrotoxicity. The inhibition of TNF-alpha production may be mediated via stabilization of I kappa B.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Antineoplastic Agents / toxicity*
  • Apoptosis / drug effects
  • Cisplatin / toxicity*
  • Drug Interactions
  • Gene Expression / drug effects
  • I-kappa B Proteins / metabolism
  • Intercellular Adhesion Molecule-1 / genetics
  • Kidney Diseases / chemically induced
  • Kidney Diseases / drug therapy*
  • Kidney Diseases / physiopathology
  • Kidney Tubules, Proximal / drug effects
  • Kidney Tubules, Proximal / physiology
  • Leukocytes / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • NF-kappa B / metabolism
  • Receptors, Tumor Necrosis Factor / genetics
  • Salicylates / pharmacology*
  • Tumor Necrosis Factor-alpha / genetics*
  • Tumor Necrosis Factor-alpha / metabolism
  • Up-Regulation


  • Anti-Inflammatory Agents, Non-Steroidal
  • Antineoplastic Agents
  • I-kappa B Proteins
  • NF-kappa B
  • Receptors, Tumor Necrosis Factor
  • Salicylates
  • Tumor Necrosis Factor-alpha
  • Intercellular Adhesion Molecule-1
  • Cisplatin