Pore-forming epsilon toxin causes membrane permeabilization and rapid ATP depletion-mediated cell death in renal collecting duct cells
Pore-forming epsilon toxin causes membrane permeabilization and rapid ATP depletion-mediated cell death in renal collecting duct cells
复制标题
DOI：
10.1152/ajprenal.00199.2007
复制
发表时间：
2007-09-01
影响因子：
4.2
通讯作者：
Vandewalle, A.
中科院分区：
文献类型：
--
作者：
Chassin, C.;Bens, M.;Vandewalle, A.
形成孔的epsilon毒素引起肾集管细胞的膜通透性和快速ATP消耗介导的细胞死亡。[J] .中华医学杂志，2009,31(4):557 - 557。首次发表于2007年6月13日；doi: 10.1152 / ajprenal.00199.2007。产气荚膜梭菌毒素（ET）是一种强效的成孔细胞毒素，可引起牲畜致命的肠毒血症。ET在脑和肾积聚，特别是在肾远端收集管。ET结合和寡聚在耐洗涤剂膜（DRMs）微域并导致细胞死亡。然而，膜通透性与细胞死亡之间的因果关系尚不清楚。在这里，我们发现ET在肾mpkCCDc（14）收集管细胞的质膜DRMs中结合并形成220-kDa不溶性复合物。磷脂酰肌醇特异性磷脂酶C不影响ET复合物的结合或形成，这表明ET受体不是GPI锚定的。ET诱导滤膜上生长的融合细胞的经上皮阻力和电位呈剂量依赖性下降，短暂刺激Na+吸收，诱导向内离子电流和[Ca-2 (+)] i的持续上升。ET还诱导细胞ATP的快速消耗，并刺激amp激活的蛋白激酶，一种代谢敏感的丝氨酸/苏氨酸激酶。ET还诱导线粒体膜渗透和线粒体核凋亡诱导因子的易位，凋亡诱导因子是一种有效的不依赖于caspase的细胞死亡效应因子。最后，ET诱导的细胞坏死的特征是细胞核大小明显减少，但没有DNA断裂。甲基- β -环糊精对DRM的破坏破坏了ET的寡聚化，并显著减少了Na（+）和[Ca2 (+)] i的内流，但没有损害由毒素引起的ATP消耗和细胞死亡。这些结果表明，ET引起肾集管细胞快速坏死，并证实ATP消耗介导的细胞死亡与毒素引起的质膜通透性和离子扩散没有严格的相关性。
Pore-forming epsilon toxin causes membrane permeabilization and rapid ATP depletion-mediated cell death in renal collecting duct cells. Am J Physiol Renal Physiol 293: F927-F937, 2007. First published June 13, 2007; doi:10.1152/ajprenal.00199.2007.- Clostridium perfringens epsilon toxin ( ET) is a potent pore-forming cytotoxin causing fatal enterotoxemia in livestock. ET accumulates in brain and kidney, particularly in the renal distal-collecting ducts. ET binds and oligomerizes in detergent-resistant membranes (DRMs) microdomains and causes cell death. However, the causal linkage between membrane permeabilization and cell death is not clear. Here, we show that ET binds and forms 220-kDa insoluble complexes in plasma membrane DRMs of renal mpkCCDc(14) collecting duct cells. Phosphatidylinositol-specific phospholipase C did not impair binding or the formation of ET complexes, suggesting that the receptor for ET is not GPI anchored. ET induced a dose-dependent fall in the transepithelial resistance and potential in confluent cells grown on filters, transiently stimulated Na+ absorption, and induced an inward ionic current and a sustained rise in [ Ca-2 (+)] i. ET also induced rapid depletion of cellular ATP, and stimulated the AMP-activated protein kinase, a metabolic-sensing Ser/Thr kinase. ET also induced mitochondrial membrane permeabilization and mitochondrial-nuclear translocation of apoptosis-inducing factor, a potent caspase-independent cell death effector. Finally, ET induced cell necrosis characterized by a marked reduction in nucleus size without DNA fragmentation. DRM disruption by methyl-beta-cyclodextrin impaired ET oligomerization, and significantly reduced the influx of Na (+) and [ Ca2 (+)] i, but did not impair ATP depletion and cell death caused by the toxin. These findings indicate that ET causes rapid necrosis of renal collecting duct cells and establish that ATP depletion-mediated cell death is not strictly correlated with the plasma membrane permeabilization and ion diffusion caused by the toxin.