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

G Ramesh, WB Reeves - The Journal of clinical …, 2002 - Am Soc Clin Investig
The Journal of clinical investigation, 2002Am Soc Clin Investig
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 …
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.
The Journal of Clinical Investigation