Protection Against Cold Storage-Induced Renal Tubular Cell Apoptosis.
Protection Against Cold Storage-Induced Renal Tubular Cell Apoptosis.
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DOI：
10.1097/tp.0000000000000774
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发表时间：
2015-11
期刊：
影响因子：
6.2
通讯作者：
Jani A
中科院分区：
文献类型：
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作者：
Jain S;Keys D;Ljubanovic D;Edelstein CL;Jani A
供肾长期冷藏与肾小管细胞凋亡和caspase-3活化相关我们以前已经表明，泛半胱天冬酶抑制剂防止冷储存相关的肾小管细胞凋亡。由于泛半胱天冬酶抑制剂的非特异性，其阻断所有半胱天冬酶，包括促炎性半胱天冬酶-1，特异性半胱天冬酶-3抑制剂在冷藏期间的作用是未知的。X连锁凋亡抑制剂（XIAP）是最有效的天然存在的特异性caspase-3抑制剂。我们假设长时间的冷藏会降低XIAP，而用新化合物UCF-101上调XIAP会防止半胱天冬酶-3活化和肾小管细胞凋亡。将来自C57 BL/6小鼠的LLC-PK 1肾小管细胞和整个肾脏在有或没有UCF-101的情况下进行长时间的冷藏，并检查XIAP、半胱天冬酶-3和肾小管细胞凋亡。体外冻存组肾小管上皮细胞XIAP表达显著降低，凋亡率、caspase-3蛋白表达及活性显著升高。UCF-101处理显著增加XIAP，显著降低capsase-3蛋白和活性，并保护细胞凋亡。为了确定治疗意义，将整个肾脏与UCF-101一起长期冷藏。UCF-101显著增加供体肾中的XIAP，并防止细胞凋亡。体外肾小管细胞和离体全小鼠肾脏的长期冷藏与XIAP的丢失和随后的肾小管细胞凋亡相关。UCF-101在体外和离体长期冷藏期间防止XIAP的损失，并且与显著减少的肾小管细胞凋亡相关。UCF-101可能代表了一种有吸引力的方法来改善器官保存。
Prolonged cold storage of donor kidneys is associated with tubular cell apoptosis and caspase-3 activation. We have previously shown that pan-caspase inhibition prevents cold storage associated tubular apoptosis. Due to the non-specific nature of pan-caspase inhibitors, which block all caspases including pro-inflammatory caspase-1, the effect of specific caspase-3 inhibition during cold storage is unknown. X-linked inhibitor of apoptosis (XIAP) is the most potent naturally occurring specific inhibitor of caspase-3. We hypothesized that prolonged cold storage would decrease XIAP, while upregulation of XIAP with the novel compound UCF-101, would protect against caspase-3 activation and tubular cell apoptosis. LLC-PK1 tubular cells and whole kidneys from C57BL/6 mice were subjected to prolonged cold storage with or without UCF-101, and examined for XIAP, caspase-3, and tubular apoptosis. Tubular cells subjected to prolonged cold storage in vitro demonstrated significantly decreased XIAP, and significantly increased apoptosis, caspase-3 protein and activity. UCF-101 treatment significantly increased XIAP, significantly decreased capsase-3 protein and activity, and protected against apoptosis. To determine the therapeutic significance, whole kidneys were subjected to prolonged cold storage with UCF-101. UCF-101 significantly increased XIAP in donor kidneys and protected against apoptosis. Prolonged cold storage of tubular cells in vitro and whole mouse kidneys ex vivo is associated with loss of XIAP and subsequent tubular cell apoptosis. UCF-101 protects against the loss of XIAP during prolonged cold storage both in vitro and ex vivo, and is associated with significantly reduced tubular cell apoptosis. UCF-101 may represent an attractive approach to improve organ preservation.