P53 Contributes to Cisplatin Induced Renal Oxidative Damage via Regulating P66shc and MnSOD
P53 Contributes to Cisplatin Induced Renal Oxidative Damage via Regulating P66shc and MnSOD
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P53 通过调节 P66shc 和 MnSOD 促进顺铂诱导的肾氧化损伤
DOI：
10.1159/000430247
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发表时间：
2015-10
影响因子：
--
通讯作者：
邢昌赢
中科院分区：
文献类型：
--
作者：
邢昌赢
背景/目的：顺铂广泛用于恶性肿瘤的治疗。然而，其主要限制是剂量依赖性肾毒性的发展。顺铂引起肾损害的确切机制尚不清楚。先前的研究证实了线粒体ROS （mtROS）在顺铂肾毒性发病机制中的核心作用。本研究旨在探讨mtROS调控顺铂肾毒性的机制。方法：采用qPCR和western blot方法检测HK2细胞中p53、MnSOD和p66shc的mRNA和蛋白水平。DCFDA和MitoSOX染色法检测mtROS水平。分别采用CCK-8法、TUNEL法和流式细胞术检测细胞活力和细胞凋亡。使用sirna敲低p53和p66shc的表达，观察随后的变化。采用顺铂致急性肾损伤小鼠模型进行体内实验，验证体外实验结果。结果：在HK2细胞中，顺铂暴露降低MnSOD，增加p53和p66shc的表达。mntpap是一种MnSOD模拟物，可阻断顺铂诱导的mtROS的产生和细胞损伤。P66shc和p53 sirna使肾细胞抵抗顺铂诱导的mtROS产生和细胞死亡。此外，p53的敲除恢复了MnSOD并抑制了p66shc。与这些结果一致，我们发现p53抑制剂通过调节顺铂处理小鼠肾脏的MnSOD和p66shc来减少顺铂诱导的氧化应激和细胞凋亡。结论：我们的研究确定p53信号的激活是一种潜在的策略，可以减少顺铂治疗相关的肾毒性，因此，拓宽了这种化疗药物的治疗窗口。
Background/Aims: Cisplatin is widely used to treat malignancies. However, its major limitation is the development of dose-dependent nephrotoxicity. The precise mechanisms of cisplatin-induced kidney damage remain unclear. Previous study demonstrated the central role of mitochondrial ROS (mtROS) in the pathogenesis of cisplatin nephrotoxicity. The purpose of this study was to explore the mechanism of mtROS regulation in cisplatin nephrotoxicity. Methods: p53, MnSOD and p66shc were detected at mRNA and protein levels by qPCR and western blot in HK2 cells. mtROS levels were determined by DCFDA and MitoSOX staining. Cell viability and cell apoptosis were accessed by CCK-8 assay, TUNEL assay and flow cytometry, respectivesly. siRNAs were used to knock down p53 and p66shc expression and subsequent changes were observed. In vivo assays using a mouse model of cisplatin-induced acute kidney injury were used to validate the in vitro results. Results: In HK2 cells, cisplatin exposure decreased the MnSOD and increased the expression of p53 and p66shc. MnTBAP, a MnSOD mimic, blocked cisplatin-induced the generation of mtROS and cell injury. P66shc and p53 siRNAs rendered renal cells resistant to cisplatin-induced mtROS production and cell death. Furthermore, knockdown of p53 restored MnSOD and inhibiting p66shc. Consistent with these results, we revealed that p53 inhibitor reduced cisplatin-induced oxidative stress and apoptosis by regulating MnSOD and p66shc in the kidney of cisplatin-treated mice. Conclusion: Our study identifies activation of p53 signalling as a potential strategy for reducing the nephrotoxicity associated with cisplatin treatments and, as a result, broadens the therapeutic window of this chemotherapeutic agent.
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影响因子：
3.7
作者：
Chen J;Wang W;Zhang Q;Li F;Lei T;Luo D;Zhou H;Yang B
通讯作者：
Yang B
影响因子：
13.6
作者：
Davis, CA;Nick, HS;Agarwal, A
通讯作者：
Agarwal, A
影响因子：
8
作者：
Trinei, M;Giorgio, M;Pelicci, PG
通讯作者：
Pelicci, PG
DOI：
10.1152/ajprenal.00230.2007
发表时间：
2007-10-01
影响因子：
4.2
作者：
Wei, Qingqing;Dong, Guie;Dong, Zheng
通讯作者：
Dong, Zheng
影响因子：
3.7
作者：
Marullo R;Werner E;Degtyareva N;Moore B;Altavilla G;Ramalingam SS;Doetsch PW
通讯作者：
Doetsch PW