Mitochondria targeted peptide SS-31 prevent on cisplatin-induced acute kidney injury via regulating mitochondrial ROS-NLRP3 pathway.,Biomedicine & Pharmacotherapy

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Mitochondria targeted peptide SS-31 prevent on cisplatin-induced acute kidney injury via regulating mitochondrial ROS-NLRP3 pathway.
Biomedicine & Pharmacotherapy ( IF 6.9 ) Pub Date : 2020-07-24 , DOI: 10.1016/j.biopha.2020.110521
Shi-Kun Yang ₁ , Ya-Chun Han ₂ , Jin-Rong He ₁ , Ming Yang ₂ , Wei Zhang ₁ , Ming Zhan ₃ , Ai-Mei Li ₁ , Liu Li ₁ , Na-Song ₁ , Yu-Ting Liu ₁ , Xue-Qin Wu ₁ , Qin Zhang ₄ , Jian-Wen Wang ₁ , Hao Zhang ₁

Affiliation

Objective

This study aimed to assess the effect and mechanism of SS31 on cisplatin-induced acute kidney injury (CP-AKI) both in vivo and in vitro.

Method

Male mices and HK-2 cells were treated using cisplatin to establish models of CP-AKI. 32 C57BL/6 mices were randomly divided into four groups (control group, CP group, CP + normal saline group, CP + SS-31 group). Cisplatin was intraperitoneally injected once to the mice (25 mg/kg). SS31 was administrated for 10 days at dosages of 10 mg/kg per day. Kidney histological changes and level of reactive oxygen species(ROS) were detected. In vitro studies, HK-2 cells were incubated with cisplatin (50 u M) or combimed with SS-31(100 u M), the level of mitochondrial ROS, apoptosis rate and the the expression of NLRP3, Caspase-1 and IL-1β were tested.

Results

Renal tubulointerstitial apoptosis and oxidative stress were significantly increased in CP-AKI mice. Cisplatin caused elevation of serum creatinine (Scr), blood urea nitrogen (BUN) levels and enhanced IL-1β, caspase1 and NLRP3 expression, the electron microscopy examination showed mitochondria cristae swelling, mitochondrial spheres and partial ridge breakdown in renal tubular cell of CP-AKI mice. SS31 treatment could effectively suppress mitochondrial ROS, ameliorate these lesions and decrease the expression of NLRP3, IL-1β and Caspase1. In vitro studies, SS31 could restored the level of mitochondrial ROS and downregulate apoptosis rate in HK-2 cells, moreover, the elevated expression of NLRP3, IL-1β and Caspase-1were restored.

Conclusion

SS31 could protect CP-AKI in mices, which might be due to an anti-oxidative and anti-apoptotic action via regulating mitochondrial ROS-NLRP3 pathway. NLRP3 inflammasome might be considered as a novel therapeutic target of CP-AKI.

中文翻译：

线粒体靶向肽SS-31通过调节线粒体ROS-NLRP3途径防止顺铂诱导的急性肾脏损伤。

目的

这项研究旨在评估SS31在体内和体外对顺铂诱导的急性肾损伤（CP-AKI）的作用和机制。

方法

用顺铂处理雄性小鼠和HK-2细胞以建立CP-AKI模型。将32只C57BL / 6小鼠随机分为四组（对照组，CP组，CP +生理盐水组，CP + SS-31组）。腹膜内一次向小鼠腹膜内注射顺铂（25 mg / kg）。SS31以每天10 mg / kg的剂量给药10天。检测肾脏的组织学变化和活性氧水平。在体外研究中，将HK-2细胞与顺铂（50 u M）孵育或与SS-31（100 u M）组合，线粒体ROS水平，凋亡率以及NLRP3，Caspase-1和IL-的表达测试了1β。

结果

CP-AKI小鼠的肾小管间质细胞凋亡和氧化应激显着增加。顺铂引起血清肌酐（Scr）升高，血尿素氮（BUN）水平升高和IL-1β，caspase1和NLRP3表达增强，电子显微镜检查显示CP-的肾小管细胞中的线粒体cr肿胀，线粒体球和部分破裂AKI小鼠。SS31治疗可有效抑制线粒体ROS，改善这些损伤并降低NLRP3，IL-1β和Caspase1的表达。在体外研究中，SS31可以恢复HK-2细胞的线粒体ROS水平并下调其凋亡率，而且还可以恢复NLRP3，IL-1β和Caspase-1的高表达。