Cisplatin-induced nephrotoxicity is mediated by tumor necrosis factor-alpha produced by renal parenchymal cells.
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.
Zhang
B
B
Division of Nephrology, Department of Medicine, Penn State Milton S, Hershey Medical Center and College of Medicine, Hershey, Pennsylvania 17033, USA.
Ramesh
G
G
Norbury
C C
CC
Reeves
W B
WB
D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology; D001806:Blood Urea Nitrogen; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D002678:Chimera / Q000235:genetics; D002945:Cisplatin / Q000009:adverse effects* / Q000494:pharmacology; D003404:Creatinine / Q000097:blood; D016207:Cytokines / Q000652:urine; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D005919:Glomerular Filtration Rate / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009399:Nephrons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D016207:Cytokines; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D003404:Creatinine; D002945:Cisplatin