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首页> 外文期刊>American Journal of Physiology >Apoptosis by Cd2+ or CdMT in proximal tubule cells: different uptake routes and permissive role of endo/lysosomal CdMT uptake.
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Apoptosis by Cd2+ or CdMT in proximal tubule cells: different uptake routes and permissive role of endo/lysosomal CdMT uptake.

机译：Cd2 +或CdMT在近端小管细胞中的凋亡：不同的摄取途径和内/溶酶体CdMT摄取的允许作用。

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The mechanisms of cadmium-metallothionein (CdMT) uptake and toxicity in proximal tubule (PT) cells are not well understood. The effects of 10 microM CdCl2 or Cd7MT-1 (MT-1 saturated with 10 microM CdCl2) on 109Cd2+ uptake, viability, and MT levels of cultured rat PT cells were investigated. Apical 109Cd2+ uptake was measured in confluent monolayers, apoptosis was assessed with Hoechst 33342, and intracellular MT levels were monitored by immunofluorescence and quantitative morphometry. 109Cd2+ uptake into PTC increased over time and plateaued at 24 h. 109Cd7MT-1 uptake was delayed but reached a similar magnitude after 40 h. With Cd2+, apoptosis occurred within 4 h, peaked at 24 h, and declined at 48-72 h. Cd7MT-1 induced apoptosis after 24-36 h, reaching similar levels as with Cd2+ after 48 h. Cd2+ and Cd7MT-1 significantly increased intracellular MT immunoreactivity after 20 and 4 h, respectively. The weak base chloroquine and the inhibitor of phosphatidylinositol 3-kinases, LY-294002, selectively inhibited the effects of Cd7MT-1 on MT immunoreactivity and apoptosis. PT cells accumulated 109Cd7MT-1 in membrane vesicles associated with the late endo/lysosomal marker LAMP1 but less with the early endosomal marker Rab5a, which was abolished by chloroquine or LY-294002. Thus development of apoptosis followed the uptake kinetics of Cd2+ and Cd7MT-1. Endo/lysosomal inhibitors prevented uptake of Cd7MT-1 into endo/lysosomes and apoptosis but had no effect on these parameters with Cd2+, suggesting that apoptosis of PT cells is triggered by free cytosolic Cd2+, either by direct apical transport or by translocation of free Cd2+ from endo/lysosomes after endocytosis of Cd7MT-1.
机译：镉-金属硫蛋白（CdMT）摄取和近端肾小管（PT）细胞毒性的机制尚不十分清楚。研究了10 microM CdCl2或Cd7MT-1（用10 microM CdCl2饱和的MT-1）对培养的大鼠PT细胞109Cd2 +摄取，生存能力和MT水平的影响。在汇合的单层中测量顶端109Cd2 +的摄取，用Hoechst 33342评估凋亡，并通过免疫荧光和定量形态学监测细胞内MT水平。 109Cd2 +对PTC的吸收随时间增加，并在24 h达到稳定。 109Cd7MT-1的吸收被延迟，但在40小时后达到相似的水平。使用Cd2 +时，凋亡在4 h内发生，在24 h达到高峰，在48-72 h下降。 Cd7MT-1在24-36小时后诱导凋亡，在48小时后达到与Cd2 +类似的水平。 Cd2 +和Cd7MT-1分别在20和4小时后显着增加了细胞内MT免疫反应性。弱碱氯喹和磷脂酰肌醇3激酶抑制剂LY-294002选择性抑制Cd7MT-1对MT免疫反应性和凋亡的影响。 PT细胞在膜囊泡中积累了109Cd7MT-1，与晚期内体/溶酶体标记物LAMP1相关，而与早期内体标记物Rab5a较少，后者被氯喹或LY-294002所废除。因此，凋亡的发展遵循Cd2 +和Cd7MT-1的吸收动力学。内溶/溶酶体抑制剂可防止Cd7MT-1摄入内吞/溶酶体并阻止细胞凋亡，但Cd2 +对这些参数没有影响，这表明PT细胞的凋亡是由游离胞浆Cd2 +触发的，通过直接心尖转运或游离Cd2 +的移位Cd7MT-1内吞后从内吞/溶酶体中提取。

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