TNF-α mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity

Ganesan Ramesh, W. Brian Reeves

Research output: Contribution to journalArticle

580 Citations (Scopus)

Abstract

The purpose of these studies was to examine the role of cytokines in the pathogenesis of cisplatin nephrotoxicity. Injection of mice with cisplatin (20 mg/kg) led to severe renal failure. The expression of cytokines, chemokines, and ICAM-1 in kidney was measured by ribonuclease protection assays and RT-PCR. We found significant upregulation of TNF-α, TGF-β, RANTES, MIP-2, MCP-1, TCA3, IL-1β, and ICAM-1 in kidneys from cisplatin-treated animals. In addition, serum, kidney, and urine levels of TNF-α measured by ELISA were increased by cisplatin. Inhibitors of TNF-α production (GM6001, pentoxifylline) and TNF-α Ab's reduced serum and kidney TNF-α protein levels and also blunted the cisplatin-induced increases in TNF-α, TGF-β, RANTES, MIP-2, MCP-1, and IL-1β, but not ICAM-1, mRNA. In addition, the TNF-α inhibitors also ameliorated cisplatin-induced renal dysfunction and reduced cisplatin-induced structural damage. Likewise, TNF-α-deficient mice were resistant to cisplatin nephrotoxicity. These results indicate cisplatin nephrotoxicity is characterized by activation of proinflammatory cytokines and chemokines. TNF-α appears to play a central role in the activation of this cytokine response and also in the pathogenesis of cisplatin renal injury.

Original languageEnglish (US)
Pages (from-to)835-842
Number of pages8
JournalJournal of Clinical Investigation
Volume110
Issue number6
DOIs
StatePublished - Sep 1 2002

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Chemokines
Cisplatin
Cytokines
Kidney
Wounds and Injuries
Intercellular Adhesion Molecule-1
Chemokine CCL5
Interleukin-1
Pentoxifylline
Ribonucleases
Serum
Renal Insufficiency
Up-Regulation
Enzyme-Linked Immunosorbent Assay
Urine
Polymerase Chain Reaction
Messenger RNA
Injections

ASJC Scopus subject areas

  • Medicine(all)

Cite this

TNF-α mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity. / Ramesh, Ganesan; Brian Reeves, W.

In: Journal of Clinical Investigation, Vol. 110, No. 6, 01.09.2002, p. 835-842.

Research output: Contribution to journalArticle

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