Cisplatin-induced nephrotoxicity is mediated by tumor necrosis factor-alpha produced by renal parenchymal cells

Kidney Int. 2007 Jul;72(1):37-44. doi: 10.1038/ Epub 2007 Mar 28.


Cisplatin is a chemotherapeutic agent that induces tumor necrosis factor-alpha (TNF-alpha) production in many cell types with unfortunate renal toxicity. We sought to determine the contributions of renal parenchymal cells and bone marrow-derived immune cells to the pathogenesis of cisplatin-induced renal injury in vivo. To do this we created chimeric mice in which the bone marrow was ablated and replaced with donor bone marrow cells from wild-type or from TNF-alpha knockout mice. Six weeks after reconstitution, the chimeric mice were treated with cisplatin and renal structural and functional parameters were measured. Chimeras with kidneys of wild-type animals all developed significant renal failure after 72 h of cisplatin treatment regardless of the immune cell source. Chimeras with kidneys of TNF-alpha knockout mice showed significantly less renal dysfunction (blood urea nitrogen, serum creatinine, and glomerular filtration rate), renal histologic injury, and serum TNF-alpha levels; again regardless of the immune cell source. Urinary excretion of several proinflammatory cytokines was lower in the wild-type bone marrow-knockout kidney chimera mouse than in wild-type background mice. Our results indicate that a substantial portion of circulating and urinary TNF-alpha is derived from nonimmune cells after cisplatin administration. We conclude that the production of TNF-alpha by renal parenchymal cells, rather than by bone marrow-derived infiltrating immune cells, is responsible for cisplatin-induced nephrotoxicity.

Publication types

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

MeSH terms

  • Acute Kidney Injury / chemically induced*
  • Acute Kidney Injury / metabolism
  • Acute Kidney Injury / pathology*
  • Animals
  • Antineoplastic Agents / adverse effects*
  • Antineoplastic Agents / pharmacology
  • Blood Urea Nitrogen
  • Bone Marrow Cells / immunology
  • Bone Marrow Cells / metabolism
  • Chimera / genetics
  • Cisplatin / adverse effects*
  • Cisplatin / pharmacology
  • Creatinine / blood
  • Cytokines / urine
  • Disease Models, Animal
  • Gene Expression Regulation / drug effects
  • Glomerular Filtration Rate / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nephrons / drug effects
  • Nephrons / metabolism*
  • Nephrons / pathology
  • Receptors, Tumor Necrosis Factor / genetics
  • Receptors, Tumor Necrosis Factor / metabolism
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism*


  • Antineoplastic Agents
  • Cytokines
  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factor-alpha
  • Creatinine
  • Cisplatin