Cisplatin-induced nephrotoxicity is mediated by tumor necrosis factor-α produced by renal parenchymal cells
Cisplatin-induced nephrotoxicity is mediated by tumor necrosis factor-α produced by renal parenchymal cells
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DOI：
10.1038/sj.ki.5002242
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发表时间：
2007-07-01
影响因子：
19.6
通讯作者：
Reeves, W. B.
中科院分区：
文献类型：
--
作者：
Zhang, B.;Ramesh, G.;Reeves, W. B.
顺铂是一种化学治疗剂，可诱导许多细胞类型产生肿瘤坏死因子-α（TNF-α），并具有不幸的肾毒性。我们试图确定肾实质细胞和骨髓源性免疫细胞的贡献，顺铂诱导的肾损伤的发病机制在体内。为了做到这一点，我们创造了嵌合小鼠，其中骨髓被消融，并替换为来自野生型或TNF-α敲除小鼠的供体骨髓细胞。重建后6周，用顺铂处理嵌合小鼠，并测量肾脏结构和功能参数。与野生型动物的肾脏嵌合体在顺铂治疗72小时后均发生了显著的肾衰竭，无论免疫细胞来源如何。与TNF-α基因敲除小鼠的肾脏嵌合体显示出显著更少的肾功能障碍（血尿素氮，血清肌酐和肾小球滤过率），肾组织学损伤和血清TNF-α水平;再次无论免疫细胞来源。几种促炎细胞因子的尿排泄在野生型骨髓敲除肾嵌合体小鼠中比在野生型背景小鼠中低。我们的研究结果表明，相当大一部分的循环和尿TNF-α是来自非免疫细胞后，顺铂管理。我们的结论是，肾实质细胞产生的TNF-α，而不是骨髓来源的浸润性免疫细胞，是顺铂诱导的肾毒性。
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.