Blockade of KCa3.1 potassium channels protects against cisplatin-induced acute kidney injury
Blockade of KCa3.1 potassium channels protects against cisplatin-induced acute kidney injury
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DOI：
10.1007/s00204-015-1607-5
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发表时间：
2016-09-01
影响因子：
6.1
通讯作者：
Pao, Li-Heng
中科院分区：
文献类型：
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作者：
Chen, Cheng-Lung;Liao, Jiunn-Wang;Pao, Li-Heng
肾小管细胞凋亡在顺铂诱导的急性肾损伤（阿基）发病机制中起重要作用。尽管KCa3.1（一种钙激活钾通道）参与细胞凋亡，但其参与顺铂诱导的阿基尚不清楚。在这里，我们发现顺铂治疗引发了早期诱导KCa3.1表达与HK-2细胞凋亡，肾小管损伤的发展，和凋亡的小鼠。高选择性KCa3.1阻断剂TRAM-34可抑制顺铂诱导的HK-2细胞凋亡。我们进一步评估了KCa3.1是否在基因敲除和药理学阻断小鼠模型中介导顺铂诱导的阿基。KCa3.1缺乏减少了顺铂治疗的KCa3.1（-/-）小鼠肾功能丧失、肾小管损伤和凋亡标记物caspase-3的诱导。TRAM-34对KCa3.1的药理学阻断类似地减弱了小鼠中顺铂诱导的阿基。此外，我们剖析了通过KCa3.1阻断顺铂诱导的细胞凋亡减少的机制。我们发现KCa 3.1阻断剂减弱了顺铂治疗后细胞色素c的释放和内源性凋亡介质Bax、巴克和caspase-9的增加。KCa3.1阻断抑制顺铂诱导的内质网（ER）应激介质caspase-12的激活，这是独立的钙依赖性蛋白酶m-calpain激活。总之，KCa3.1阻断通过干扰内在凋亡和ER应激相关介质来减弱凋亡，从而保护顺铂诱导的阿基，为预防顺铂诱导的阿基提供了潜在靶点。
Tubular cell apoptosis significantly contributes to cisplatin-induced acute kidney injury (AKI) pathogenesis. Although KCa3.1, a calcium-activated potassium channel, participates in apoptosis, its involvement in cisplatin-induced AKI is unknown. Here, we found that cisplatin treatment triggered an early induction of KCa3.1 expression associated with HK-2 cell apoptosis, the development of renal tubular damage, and apoptosis in mice. Treatment with the highly selective KCa3.1 blocker TRAM-34 suppressed cisplatin-induced HK-2 cell apoptosis. We further assessed whether KCa3.1 mediated cisplatin-induced AKI in genetic knockout and pharmacological blockade mouse models. KCa3.1 deficiency reduced renal function loss, renal tubular damage, and the induction of the apoptotic marker caspase-3 in the kidneys of cisplatin-treated KCa3.1(-/-) mice. Pharmacological blockade of KCa3.1 by TRAM-34 similarly attenuated cisplatin-induced AKI in mice. Furthermore, we dissected the mechanisms underlying cisplatin-induced apoptosis reduction via KCa3.1 blockade. We found that KCa3.1 blockade attenuated cytochrome c release and the increase in the intrinsic apoptotic mediators Bax, Bak, and caspase-9 after cisplatin treatment. KCa3.1 blocking inhibited the cisplatin-induced activation of the endoplasmic reticulum (ER) stress mediator caspase-12, which is independent of calcium-dependent protease m-calpain activation. Taken together, KCa3.1 blockade protects against cisplatin-induced AKI through the attenuation of apoptosis by interference with intrinsic apoptotic and ER stress-related mediators, providing a potential target for the prevention of cisplatin-induced AKI.