Initiation of caspase-independent death in mouse mesangial cells by Cd2+:: Involvement of p38 kinase and CaMK-II
Initiation of caspase-independent death in mouse mesangial cells by Cd2+:: Involvement of p38 kinase and CaMK-II
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DOI：
10.1002/jcp.21499
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发表时间：
2008-11-01
影响因子：
5.6
通讯作者：
Templeton, Douglas M.
中科院分区：
文献类型：
--
作者：
Liu, Ying;Templeton, Douglas M.
镉（Cd）是一种有毒金属，对细胞信号传导和细胞死亡具有多种影响。我们研究了在无血清条件下镉对静止小鼠系膜细胞的影响。镉通过膜联蛋白V+状态诱导细胞死亡超过6小时，而不引起碘化丙啶的摄取。分别称为凋亡和凋亡样死亡。很少或没有观察到坏死，细胞死亡是半胱天冬酶独立的，并与凋亡诱导因子AIF的核转位有关。我们以前表明，Cd 2+增加了ERK和CaMK-Ⅱ的磷酸化，CaMK-Ⅱ的活化增加了ERK独立的细胞死亡。在这里，我们表明，镉增加JNK和p38激酶磷酸化，抑制p38-但不是JNK-通过抑制细胞凋亡增加细胞活力，优先于凋亡样死亡。无论是p38激酶还是CaMK-II抑制都不能防止线粒体膜电位Psi的降低，这表明激酶介导的死亡要么独立于线粒体途径，要么涉及线粒体途径下游的事件。然而，抗氧化剂N-乙酰半胱氨酸（NAC）和线粒体膜稳定剂环孢菌素A（CsA）部分保护Psi，抑制p38激酶的激活，并部分保护细胞免受Cd 2+诱导的死亡。CsA作用于细胞凋亡，NAC作用于细胞凋亡样死亡。谷胱甘肽合成的抑制加剧了Cd 2+依赖的细胞过氧化物的增加，并有利于凋亡样死亡超过凋亡。这些细胞死亡模式的caspase独立性是暴乱的，因为在系膜细胞中没有这种机制：当它们在血清存在下暴露于Cd 2+较长时间时，caspase-3和PARP被切割，caspase抑制是保护性的。我们的结论是，镉可以通过多种途径杀死系膜细胞，包括半胱天冬酶依赖性和非依赖性凋亡和类凋亡。坏死不明显。Cd 2+对p38激酶和CaMK-II的激活与不依赖于油的线粒体不稳定的半胱天冬酶非依赖性细胞凋亡有关。
Cadmium (Cd) is a toxic metal with multiple effects on cell signaling and cell death. We studied the effects of Cd2+ on quiescent mouse mesangial cells in serum-free conditions. Cadmium induces cell death over 6 h through annexin V+ states without or with causing uptake of propidium iodide. termed apoptotic and apoptosis-like death, respectively. Little or no necrosis is observed, and cell death is caspase-independent and associated with nuclear translocation of the apoptosis-inducing factor, AIF We previously showed that Cd2+ increased phosphorylation of Erk and CaMK-II, and CaMK-II activation increased cell death in an Erk-independent manner. Here we demonstrate that Cd2+ increases Jnk and p38 kinase phosphorylation, and inhibition of p38-but not of Jnk-increases cell viability by suppressing apoptosis in preference to apoptosis-like death. Neither p38 kinase nor CaMK-II inhibition protects against a decrease in mitochondrial membrane potential, Psi, indicating that kinase-mediated death is either independent of, or involves events downstream of a mitochondrial pathway. However, both the antioxidant N-acetyl cysteine (NAC) and the mitochondrial membrane-stabilizing agent cyclosporine A (CsA) partially preserve Psi, suppress activation of p38 kinase, and partially protect the cells from Cd2+-induced death. Whereas the effect of CsA is on apoptosis, NAC acts oil apoptosis-like death. Inhibition of glutathione synthesis exacerbates a Cd2+-dependent increase in cellular per-oxides and favors apoptosis-like death over apoptosis. The caspase-independence of these modes of cell death is riot due to an absence of this machinery in the mesangial cells: when they are exposed to Cd2+ for longer periods in the presence of serum, procaspase-3 and PARP are cleaved and caspase inhibition is protective. We conclude that Cd2+ can kill mesangial cells by multiple pathways, including caspase-dependent and -independent apoptotic and apoptosis-like death. Necrosis is not prominent. Activation of p38 kinase and of CaMK-II by Cd2+ are associated with caspase-independent apoptosis that is not dependent oil mitochondrial destabilization.