title: TNF-alpha mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity.
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-alpha, TGF-beta, RANTES, MIP-2, MCP-1, TCA3, IL-1beta, and ICAM-1 in kidneys from cisplatin-treated animals. In addition, serum, kidney, and urine levels of TNF-alpha measured by ELISA were increased by cisplatin. Inhibitors of TNF-alpha production (GM6001, pentoxifylline) and TNF-alpha Ab's reduced serum and kidney TNF-alpha protein levels and also blunted the cisplatin-induced increases in TNF-alpha, TGF-beta, RANTES, MIP-2, MCP-1, and IL-1beta, but not ICAM-1, mRNA. In addition, the TNF-alpha inhibitors also ameliorated cisplatin-induced renal dysfunction and reduced cisplatin-induced structural damage. Likewise, TNF-alpha-deficient mice were resistant to cisplatin nephrotoxicity. These results indicate cisplatin nephrotoxicity is characterized by activation of proinflammatory cytokines and chemokines. TNF-alpha appears to play a central role in the activation of this cytokine response and also in the pathogenesis of cisplatin renal injury.
authors.affiliation: Division of Nephrology, Penn State College of Medicine, Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033, USA.
authors.forename: Ganesan
authors.initials: G
authors.lastname: Ramesh
authors.forename: W Brian
authors.initials: WB
authors.lastname: Reeves
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D002945:Cisplatin / Q000633:toxicity*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004151:Dipeptides / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000293:injuries / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010431:Pentoxifylline / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D018925:Chemokines; D016207:Cytokines; D004151:Dipeptides; D004791:Enzyme Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D014409:Tumor Necrosis Factor-alpha; D002945:Cisplatin; D010431:Pentoxifylline