Cadmium inhibits both intrinsic and extrinsic apoptotic pathways in renal mesangial cells
Cadmium inhibits both intrinsic and extrinsic apoptotic pathways in renal mesangial cells
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DOI：
10.1152/ajprenal.00067.2005
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发表时间：
2006-05-01
影响因子：
4.2
通讯作者：
Templeton, DM
中科院分区：
文献类型：
--
作者：
Gunawardana, CG;Martinez, RE;Templeton, DM
镉是一种强有力的肾毒素，已被证明可以诱导某些细胞的凋亡，但在某些情况下也可以防止凋亡。在肾小球损伤的几种临床情况和实验模型中，系膜细胞的病理性增殖之后是涉及系膜细胞凋亡的解决。本实验通过外源性受体介导的途径和内源性细胞凋亡依赖的途径，研究了镉（2+）对大鼠肾小球系膜细胞凋亡的影响。喜树碱通过激活半胱天冬酶-9和半胱天冬酶依赖性切割半胱天冬酶原-3启动了内源性途径。肿瘤坏死因子-α（TNF-α）在两条途径的汇合点启动caspase-8活性和caspase-3原的裂解。然而，胱天蛋白酶原-8水平较低，胱天蛋白酶-9也响应于TNF-α而被激活，这是被称为II型细胞的特征。与TNF-α和喜树碱，同时暴露于10 μ M氯化镉（2）抑制DNA梯状，核凝聚，和pro-caspase-3裂解。它还降低了caspase-8和caspase-9的活性，阻止了caspase-8依赖的促凋亡因子Bid的裂解，并抑制了线粒体释放细胞色素c。在这个10 μ M的浓度，镉（2+）是唯一的一些金属离子中，防止DNA片段。我们的结论是，镉（2+）是抗大鼠肾小球系膜细胞凋亡，作用的机制，可能涉及一般的半胱天冬酶抑制。这可能对肾小球系膜细胞过度增殖的情况下的肾炎的解决具有后果。
Cadmium is a potent nephrotoxin that has been shown to induce apoptosis in some cells but also to prevent it under certain circumstances. In several clinical situations and experimental models of injury to the renal glomerulus, pathological proliferation of mesangial cells is followed by resolution involving mesangial cell apoptosis. We investigated the effects of Cd(2+) on rat mesangial cells induced to undergo apoptosis through either the extrinsic receptor-mediated pathway or the intrinsic mitochondrial-dependent pathway. Camptothecin initiated the intrinsic pathway with activation of caspase-9 and caspase-dependent cleavage of procaspase-3. Tumor necrosis factor-alpha (TNF-alpha) initiated caspase-8 activity and cleavage of pro-caspase-3 at the convergence point of the two pathways. However, pro-caspase-8 levels were low, and caspase-9 was also activated in response to TNF-alpha, characteristic of what have been termed type II cells. With both TNF-alpha and camptothecin, concurrent exposure to 10 mu M CdCl(2) suppressed DNA laddering, nuclear condensation, and pro-caspase-3 cleavage. It also decreased activity of both caspase-8 and caspase-9, prevented caspase-8-dependent cleavage of the proapoptotic factor Bid, and suppressed release of cytochrome c from mitochondria. At this 10-mu M concentration, Cd(2+) was unique among a number of metal ions in preventing DNA fragmentation. We conclude that Cd(2+) is anti-apoptotic in rat mesangial cells, acting by a mechanism that may involve general caspase inhibition. This may have consequences for the resolution of nephritis in situations of mesangial cell hyperproliferation.