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

TLDR

The study aimed to determine how cytokines contribute to cisplatin‑induced kidney damage. Kidney cytokine, chemokine, and ICAM‑1 expression was quantified by ribonuclease protection assays and RT‑PCR. Cisplatin caused severe renal failure and upregulated numerous cytokines and chemokines, particularly TNF‑α, and blocking or deleting TNF‑α reduced these inflammatory signals and protected against renal injury.

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.