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首页> 外文期刊>Archives of Toxicology >Effects of salubrinal on cadmium-induced apoptosis in HK-2 human renal proximal tubular cells
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Effects of salubrinal on cadmium-induced apoptosis in HK-2 human renal proximal tubular cells

机译：刺五加对镉诱导的HK-2人肾近端肾小管细胞凋亡的影响

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摘要

Cadmium exposure is known to cause endoplasmic reticulum (ER) stress. In our current study, we examined the effects of salubrinal, a selective inhibitor of eukaryotic translation initiation factor 2 subunit α (eIF2α) dephosphorylation, on apoptotic cell death and ER stress-signaling events in HK-2 human renal proximal tubular cells exposed to cadmium chloride (CdCl2). Using phase-contrast microscopy and a cell viability assay, we observed that salubrinal suppressed CdCl2-induced cellular damage and cell death. Treatment with salubrinal reduced the number of TUNEL-positive cells and the cleavages of caspase-3 and poly(ADP-ribose) polymerase, but not the cleavage of light chain 3B, indicating protection from CdCl2-induced apoptosis but not autophagy. Although eIF2α remained phosphorylated after CdCl2 exposure to salubrinal-treated HK-2 cells, the expression of activating transcription factor 4 (ATF4) and the 78 kDa glucose-regulated protein (GRP78) was not increased. On the other hand, CdCl2-induced expression of C/EBP homologous protein (CHOP) was reduced by salubrinal treatment. Expression of ATF4, an upstream regulator of GRP78 and CHOP, appeared to be a prerequisite for full protection by salubrinal against cadmium cytotoxicity, because CdCl2-induced cellular damage was not fully suppressed in ATF4-deficient cells. Phosphorylated forms of mitogen-activated protein kinases (MAPKs), including c-Jun NH2-terminal kinase (JNK), p38, and extracellular signal-regulated protein kinase (ERK), increased after CdCl2 exposure, whereas salubrinal suppressed the phosphorylation of JNK and p38 but not ERK. These results suggest that salubrinal protects CdCl2-exposed HK-2 cells from apoptosis by suppressing cell death signal transduction pathways.
机译：已知镉暴露会引起内质网（ER）应激。在我们当前的研究中，我们检查了salubrinal（真核翻译起始因子2亚基α（eIF2α）去磷酸化的选择性抑制剂）对暴露于镉的HK-2人肾近端肾小管细胞凋亡和死亡以及内质网应激信号事件的影响。氯化物（CdCl 2 ）。使用相差显微镜和细胞活力测定法，我们观察到salubrinal抑制了CdCl 2 诱导的细胞损伤和细胞死亡。金枪鱼处理减少了TUNEL阳性细胞的数量，减少了caspase-3和聚ADP-核糖聚合酶的裂解，但没有裂解轻链3B，表明对CdCl 2 诱导的保护凋亡但不自噬。尽管CdCl 2 暴露于经salulinal处理的HK-2细胞后，eIF2α仍被磷酸化，但活化转录因子4（ATF4）和78 kDa葡萄糖调节蛋白（GRP78）的表达并未增加。另一方面，CalCl处理降低了CdCl 2 诱导的C / EBP同源蛋白（CHOP）的表达。 ATF4的表达似乎是GRP78和CHOP的上游调节子，因此被Salubrinal完全保护免受镉的细胞毒性作用是先决条件，因为CdCl 2 诱导的细胞损伤在ATF4缺陷细胞中并未得到完全抑制。 CdCl 2 -末端激酶（JNK），p38和细胞外信号调节蛋白激酶（ERK）。 > 2 暴露，而salubrinal抑制JNK和p38的磷酸化，但不抑制ERK。这些结果表明，salubrinal通过抑制细胞死亡信号转导途径来保护CdCl 2 暴露的HK-2细胞免于凋亡。

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