ABSTRACT

The toxicity of cadmium (Cd) occurs through accumulation in the environment. The precise mechanism underlying Cd toxicity remains unclear. Therefore, in the present study, we studied the effects of Cd on MM55.K cells and investigated the mechanisms underlying Cd-induced cell death. CdCl2 significantly elevated apoptotic cell death, mitochondrial membrane potential (ΔΨ_m) loss, and caspase-dependent cell death. Moreover, immunoblotting results revealed that CdCl2 down-regulated the inhibitor of apoptotic protein such as survivin and Bcl-2 which led to the activation of caspase-3 and the cleavage of PARP in MM55.K cells. Besides, CdCl2 caused the up-regulation of ROS-related proteins such as HO-1 and ER stress-related proteins such as GRP78 and CHOP in MM55.K cells. CdCl2 toxicity resulted in the down-regulation of the AKT pathway that leads to the up-regulation of phosphorylated JNK and p38 in MM55.K cells. Thus, CdCl2 induce toxicity by AKT/MAPK regulation and causing ROS production, ER stress, ΔΨ_m loss, and apoptotic cell death in normal mouse renal cells.

摘要

镉 (Cd) 的毒性是通过在环境中积累而产生的。镉中毒的确切机制仍不清楚。因此，在本研究中，我们研究了 Cd 对 MM55.K 细胞的影响，并研究了 Cd 诱导细胞死亡的机制。CdCl2 显着提高凋亡细胞死亡、线粒体膜电位 (ΔΨ _m) 损失和半胱天冬酶依赖性细胞死亡。此外，免疫印迹结果显示，CdCl2 下调 survivin 和 Bcl-2 等凋亡蛋白抑制剂，导致 MM55.K 细胞中 caspase-3 的激活和 PARP 的裂解。此外，CdCl2 引起 MM55.K 细胞中 ROS 相关蛋白如 HO-1 和 ER 应激相关蛋白如 GRP78 和 CHOP 的上调。CdCl2 毒性导致 AKT 通路的下调，从而导致 MM55.K 细胞中磷酸化 JNK 和 p38 的上调。因此，CdCl2 通过 AKT/MAPK 调节诱导毒性，并在正常小鼠肾细胞中引起 ROS 产生、ER 应激、ΔΨ _m损失和凋亡细胞死亡。