Necrostatin-1 Attenuates Cisplatin-Induced Nephrotoxicity Through Suppression of Apoptosis and Oxidative Stress and Retains Klotho Expression.
Necrostatin-1 Attenuates Cisplatin-Induced Nephrotoxicity Through Suppression of Apoptosis and Oxidative Stress and Retains Klotho Expression.
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Necrostatin-1 通过抑制细胞凋亡和氧化应激减轻顺铂诱导的肾毒性并保留 Klotho 表达
DOI：
10.3389/fphar.2018.00384
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发表时间：
2018
影响因子：
5.6
通讯作者：
Ding X
中科院分区：
文献类型：
--
作者：
Ning Y;Shi Y;Chen J;Song N;Cai J;Fang Y;Yu X;Ji J;Ding X
目的：顺铂是一种有效的化疗药物，但其肾毒性极大地限制了其在临床上的应用。死亡抑素-1(NEC-1)是一种RIP1激酶的抑制剂，已有报道可抑制RIP介导的坏死性下垂。本研究旨在检测NEC-1对顺铂肾毒性的保护作用，并探讨其肾保护机制。方法：8周龄雄性C57BL/6小鼠随机分为4组：对照组、NEC-1组、顺铂组和顺铂+NEC-1组。顺铂加或不加NEC-1预处理。观察肾功能、组织学改变、坏死性下垂和细胞凋亡标记物。还检测了NF-κB途径相关蛋白、致炎细胞因子、氧化应激标志物、肾Klotho和自噬相关蛋白水平。结果：肾功能和组织学数据显示，NEC-1治疗可显著减轻顺铂所致的肾损伤。顺铂组RIPK1/RIPK3/MLKL的表达明显高于对照组(p<；0.05)，NEC-1干预后RIPK1/RIPK3/MLKL的表达明显降低(p<；0.05)。应激水平和细胞凋亡相关蛋白p-JNK、p-c-jun、p-p38、Bax/Bcl2比值和caspase-3也有类似的变化趋势。NEC-1预处理可抑制NF-κB信号转导，减少促炎细胞因子和氧化应激，上调肾Klotho和自噬相关蛋白水平。结论：NEC-1可能通过其抗坏死性下垂、抗细胞凋亡、抗炎抗氧化剂、保留Klotho表达和激活肾脏自噬作用而成为抗顺铂肾毒性的潜在治疗药物。
Aim: Cisplatin is an effective chemotherapeutic drug, but the application in clinical is greatly limited by its nephrotoxicity. Necrostatin-1 (Nec-1), an inhibitor of RIP1 kinase, has been reported to inhibit RIP-mediated necroptosis. The aim of this study is to detect the protective effects of Nec-1 on the nephrotoxicity of cisplatin and to investigate its renoprotection mechanism. Methods: 8-week-old male C57BL/6 mice were randomly assigned into four groups: Control, Nec-1, Cisplatin, and Cisplatin+Nec-1. Mice were treated with cisplatin with or without Nec-1 pre-treatment. Renal function, histological changes, necroptosis, and apoptotic markers were investigated. NFκB pathway related proteins, proinflammatory cytokines, oxidative stress markers, renal Klotho, and autophagy-related proteins levels were also examined. Results: Renal function and histological data displayed that the treatment with Nec-1 significantly attenuates cisplatin-induced renal damage. The expression of RIPK1/RIPK3/MLKL were significantly enhanced in cisplatin group as compared to the control group (p < 0.05) and was significantly reduced by pre-treatment of Nec-1 (p < 0.05). The level of stress and apoptosis-related protein, including p-JNK, p-c-Jun, p-p38, Bax/Bcl-2 ratio, and caspase-3 showed the similar trend. Pre-treatment with Nec-1 inhibit NFκB signaling, reduced proinflammatory cytokines and oxidative stress, up-regulated renal Klotho, and autophagy-related proteins levels. Conclusion: Our results suggest that Nec-1 could be a potential therapeutic drug against the cisplatin-induced nephrotoxicity through its anti-necroptosis, anti-apoptotic, anti-inflammatory anti-oxidant and retain Klotho expression and activate autophagy effects in the kidney.
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影响因子：
19.6
作者：
Linkermann, Andreas;Himmerkus, Nina;Krautwald, Stefan
通讯作者：
Krautwald, Stefan
影响因子：
3.8
作者：
Khan, Rehan;Khan, Abdul Quaiyoom;Sultana, Sarwat
通讯作者：
Sultana, Sarwat
影响因子：
19.6
作者：
Linkermann, Andreas;Braesen, Jan H.;Krautwald, Stefan
通讯作者：
Krautwald, Stefan
DOI：
10.1006/bbrc.1998.9576
发表时间：
1998-10-29
影响因子：
3.1
作者：
Ohyama, Y;Kurabayashi, M;Nagail, R
通讯作者：
Nagail, R
影响因子：
13.6
作者：
Moreno, Juan A.;Izquierdo, Maria C.;Sanz, Ana B.
通讯作者：
Sanz, Ana B.