Renal tubular Fas ligand mediates fratricide in cisplatin-induced acute kidney failure
Renal tubular Fas ligand mediates fratricide in cisplatin-induced acute kidney failure
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DOI：
10.1038/ki.2010.317
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发表时间：
2011-01-01
影响因子：
19.6
通讯作者：
Krautwald, Stefan
中科院分区：
文献类型：
--
作者：
Linkermann, Andreas;Himmerkus, Nina;Krautwald, Stefan
顺铂是许多肿瘤的标准化疗药物，不幸的是，它有一种常见的毒性，几乎三分之一的患者在单次剂量后出现肾功能障碍。顺铂所致的急性肾损伤依赖于肾小管上皮细胞和浸润性免疫细胞上表达的Fas配体(FasL)介导的Fas介导的细胞凋亡。由于FasL在T细胞中的作用已知，我们调查了其在原代肾脏细胞中的存在是否需要其毒性作用。我们发现，所有接受顺铂治疗的野生型(Wt)小鼠都在6天内死亡；然而，严重联合免疫缺陷(SCID)/米色小鼠(B-、T-和自然杀伤细胞缺陷)显示出显著的生存益处，仅有55%的死亡率，同时表现出显著的肾功能衰竭。用一种阻断FasL的单抗MFL3治疗SCID/Beige小鼠，完全恢复了在其他致命剂量顺铂后的存活，这表明除了免疫细胞外，还有另一种FasL来源。将wt小鼠新鲜分离的原代小管段与新分离的表达绿色荧光蛋白(GFP)转基因小鼠的粗大升支(TAL)段(相同的遗传背景)共同孵育，以确定FasL介导的肾小管细胞杀伤是自分泌机制还是旁分泌机制。顺铂刺激的原代片段诱导GFP标记的TAL细胞凋亡，这一作用被MFL3阻断。因此，我们的研究表明，顺铂诱导的肾病是通过FasL介导的，FasL在肾小管上有功能地表达，能够诱导邻近肾小管的细胞死亡。《国际肾脏》(2011年)79,159-178；DOI：10.1038/ki.2010.317；2010年9月1日在线发布
Cisplatin, a standard chemotherapeutic agent for many tumors, has an unfortunately common toxicity where almost a third of patients develop renal dysfunction after a single dose. Acute kidney injury caused by cisplatin depends on Fas-mediated apoptosis driven by Fas ligand (FasL) expressed on tubular epithelial and infiltrating immune cells. Since the role of FasL in T cells is known, we investigated whether its presence in primary kidney cells is needed for its toxic effect. We found that all cisplatin-treated wild-type (wt) mice died within 6 days; however, severe combined immunodeficiency (SCID)/beige mice (B-, T-, and natural killer-cell-deficient) displayed a significant survival benefit, with only 55% mortality while exhibiting significant renal failure. Treating SCID/beige mice with MFL3, a FasL-blocking monoclonal antibody, completely restored survival after an otherwise lethal cisplatin dose, suggesting another source of FasL besides immune cells. Freshly isolated primary tubule segments from wt mice were co-incubated with thick ascending limb (TAL) segments freshly isolated from mice expressing the green fluorescent protein (GFP) transgene (same genetic background) to determine whether FasL-mediated killing of tubular cells is an autocrine or paracrine mechanism. Cisplatin-stimulated primary segments induced apoptosis in the GFP-tagged TAL cells, an effect blocked by MFL3. Thus, our study shows that cisplatin-induced nephropathy is mediated through FasL, functionally expressed on tubular cells that are capable of inducing death of cells of adjacent tubules. Kidney International (2011) 79, 159-178; doi:10.1038/ki.2010.317; published online 1 September 2010