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Proteasome inhibitor MG132 reduces growth of As4.1 juxtaglomerular cells via caspase-independent apoptosis

机译:蛋白酶体抑制剂MG132通过不依赖胱天蛋白酶的凋亡减少As4.1肾小球细胞的生长

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The proteasome inhibitor MG132 has been shown to induce apoptotic cell death through the formation of reactive oxygen species (ROS). Here, we investigated the molecular mechanisms of MG132 in As4.1 juxtaglomerular cell death in relation to apoptosis and levels of ROS and glutathione (GSH). MG132 inhibited the growth of As4.1 cells with an IC50 of approximately 0.3–0.4 μM at 48 h and induced cell death, accompanied by the loss of mitochondrial membrane potential (MMP; ∆Ψm), Bcl-2 decrease, activations of caspase-3 and caspase-8, and PARP cleavage. MG132 increased intracellular ROS levels and GSH-depleted cell numbers. However, caspase inhibitors, especially Z-VAD (pan-caspase inhibitor) intensified cell growth inhibition, cell death, MMP (∆Ψm) loss, and Bcl-2 decrease in MG132-treated As4.1 cells. Z-VAD also slightly intensified increases in ROS levels and GSH depletion in MG132-treated As4.1 cells. In conclusion, MG132 reduced the growth of As4.1 cells via caspase-independent apoptosis. The changes in ROS and GSH levels by MG132 and caspase inhibitors partially influenced the growth inhibition and death of As4.1 cells.
机译:蛋白酶体抑制剂MG132已显示通过形成活性氧(ROS)诱导凋亡性细胞死亡。在这里,我们研究了MG132在As4.1肾小球细胞死亡中与细胞凋亡以及ROS和谷胱甘肽(GSH)水平相关的分子机制。 MG132抑制As4.1细胞的生长,在48 h时IC 50 约为0.3–0.4μM,并诱导细胞死亡,并伴随线粒体膜电位的丧失(MMP; ∆Ψ m ),Bcl-2减少,caspase-3和caspase-8活化以及PARP裂解。 MG132增加细胞内ROS水平和GSH耗尽的细胞数量。然而,在MG132处理的As4.1中,半胱天冬酶抑制剂,尤其是Z-VAD(泛半胱天冬酶抑制剂)增强了细胞生长抑制,细胞死亡,MMP(ΔΨ m )损失和Bcl-2降低。细胞。 Z-VAD在MG132处理的As4.1细胞中,ROS水平和GSH消耗也略有增强。总之,MG132通过不依赖caspase的凋亡减少了As4.1细胞的生长。 MG132和半胱天冬酶抑制剂对ROS和GSH水平的改变部分影响了As4.1细胞的生长抑制和死亡。

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