Ischemia/Reperfusion Induce Renal Tubule Apoptosis by Inositol 1,4,5-Trisphosphate Receptor and L-Type Ca2+ Channel Opening
Ischemia/Reperfusion Induce Renal Tubule Apoptosis by Inositol 1,4,5-Trisphosphate Receptor and L-Type Ca2+ Channel Opening
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DOI：
10.1159/000113107
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发表时间：
2008-01
影响因子：
4.2
通讯作者：
Di Wu;Xiangmei Chen;Rui Ding;Xi Qiao;Suozhu Shi;Yuansheng Xie;Q. Hong;Zhe Feng
中科院分区：
文献类型：
--
作者：
Di Wu;Xiangmei Chen;Rui Ding;Xi Qiao;Suozhu Shi;Yuansheng Xie;Q. Hong;Zhe Feng
近年来的研究表明，除L型钙通道外，内质网上的两种钙通道，即1，4，5-三磷酸肌醇受体（InsP 3R）和兰尼碱受体（RyR），可能在缺血再灌注（I/R）损伤诱导的肾小管细胞凋亡过程中发挥作用。我们用抗霉素A在体外诱导细胞I/R损伤，发现细胞内钙离子浓度升高，从而导致细胞凋亡。用尼卡地平阻断L-型钙通道或用TMB-8阻断InsP 3R可抑制细胞色素c释放，激活caspase 3并减少凋亡细胞数。然而，用丹曲洛林阻断RyR没有效果。我们进一步发现，通过L型通道的Ca 2+内流是打开InsP 3R所必需的，InsP 3R激活了从ER库释放Ca 2+的级联反应。为了在体内测试这些阻断剂，在大鼠肾I/R模型中，用尼卡地平和TMB-8预处理，而不是丹曲林，可以保护肾功能。总之，我们的结果表明，I/R损伤后，通过L型钙通道的Ca 2+内流触发从InsP 3R的Ca 2+释放，并最终诱导凋亡。InsP 3R可能成为治疗肾I/R损伤的新靶点。
Recent studies suggest that besides the L-type calcium channel, two calcium channels on the endoplasmic reticulum (ER), the inositol 1,4,5-trisphosphate receptor (InsP3R) and ryanodine receptor (RyR), may play a role in the apoptotic process of renal tubular cells induced by ischemia/reperfusion (I/R) injury. We used antimycin A to induce cell I/R injury in vitro and found an elevation of the cytosolic calcium concentration and consequently apoptosis. Blocking either the L-type calcium channel with nicardipine or the InsP3R with TMB-8 can inhibit cytochrome c release, activate caspase 3 and decrease the apoptotic cell number. However, blocking the RyR with dantrolene had no effect. We further found that Ca2+ influx through the L-type channel is needed for the opening of the InsP3R which activates a cascade of Ca2+ release from the ER store. To test these blockers in vivo, in a rat renal I/R model, pretreatment with nicardipine and TMB-8, but not dantrolene, can protect renal function. Taken together, our results suggest that after I/R injury, Ca2+ influx through the L-type calcium channel triggers the Ca2+ release from the InsP3R and finally induces apoptosis. The InsP3R could be a new target for the treatment of renal I/R injury.