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Indispensable role of mitochondria in maintaining the therapeutic potential of curcumin in acute kidney injury
Journal of Cellular and Molecular Medicine ( IF 4.3 ) Pub Date : 2021-09-16 , DOI: 10.1111/jcmm.16934
Ling Li 1, 2 , Shuyun Liu 1 , Yijie Zhou 1 , Meng Zhao 1 , Yizhuo Wang 1 , Chengshi Wang 1 , Peng Lou 1 , Rongshuang Huang 2 , Liang Ma 2 , Yanrong Lu 1 , Ping Fu 2 , Jingping Liu 1
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Acute kidney injury (AKI) is a serious disease for which effective therapeutic agents are required. The capacity of curcumin (CUR) to resolve renal inflammation/oxidative stress and mitochondrial damage has been reported, but crosstalk between these effects and the consequence of this crosstalk remain elusive. In this study, a hypoxia/reoxygenation (H/R)-induced renal tubular epithelial cell (TEC) injury model and an ischaemia/reperfusion (I/R)-induced mouse AKI model were treated with CUR with or without mitochondrial inhibitors (rotenone and FCCP) or siRNA targeting mitochondrial transcription factor A (TFAM). Changes in mitochondrial function, inflammation, the antioxidant system and related pathways were analysed. In vitro, CUR suppressed NFκB activation and cytokine production and induced NRF2/HO-1 signalling in TECs under H/R conditions. CUR treatment also reduced mitochondrial ROS (mtROS) and mitochondrial fragmentation and enhanced mitochondrial biogenesis, TCA cycle activity and ATP synthesis in damaged TECs. However, the anti-inflammatory and antioxidant effects of CUR in damaged TECs were markedly abolished upon mitochondrial disruption. In vivo, CUR treatment improved renal function and antioxidant protein (NRF2 and SOD2) expression and reduced oxidative stress (8-OHdG), tubular apoptosis/death, cytokine release/macrophage infiltration and mitochondrial damage in the kidneys of AKI mice. In vitro, the anti-inflammatory and antioxidant effects of CUR in damaged kidneys were impaired when mitochondrial function was disrupted. These results suggest mitochondrial damage is a driving factor of renal inflammation and redox imbalance. The therapeutic capacity of CUR in kidneys with AKI is primarily dependent on mitochondrial mechanisms; thus, CUR is a potential therapy for various diseases characterized by mitochondrial damage.

中文翻译:

线粒体在维持姜黄素在急性肾损伤中的治疗潜力中的不可或缺的作用

急性肾损伤 (AKI) 是一种严重的疾病,需要有效的治疗药物。姜黄素 (CUR) 解决肾脏炎症/氧化应激和线粒体损伤的能力已有报道,但这些作用之间的串扰和这种串扰的后果仍然难以捉摸。在这项研究中,缺氧/复氧 (H/R) 诱导的肾小管上皮细胞 (TEC) 损伤模型和缺血/再灌注 (I/R) 诱导的小鼠 AKI 模型在有或没有线粒体抑制剂(鱼藤酮)的情况下用 CUR 治疗。和 FCCP) 或 siRNA 靶向线粒体转录因子 A (TFAM)。分析了线粒体功能、炎症、抗氧化系统和相关途径的变化。在体外,CUR 抑制 NFκB 活化和细胞因子产生,并在 H/R 条件下诱导 TECs 中的 NRF2/HO-1 信号传导。CUR 治疗还减少了线粒体 ROS (mtROS) 和线粒体碎片,并增强了受损 TECs 中的线粒体生物合成、TCA 循环活性和 ATP 合成。然而,CUR 在受损 TECs 中的抗炎和抗氧化作用在线粒体破坏后显着消除。在体内,CUR 治疗改善了 AKI 小鼠的肾功能和抗氧化蛋白(NRF2 和 SOD2)表达,并减少了氧化应激(8-OHdG)、肾小管凋亡/死亡、细胞因子释放/巨噬细胞浸润和线粒体损伤。在体外,当线粒体功能被破坏时,CUR 在受损肾脏中的抗炎和抗氧化作用受损。这些结果表明线粒体损伤是肾脏炎症和氧化还原失衡的驱动因素。CUR 在 AKI 肾脏中的治疗能力主要取决于线粒体机制;因此,CUR 是一种潜在的治疗以线粒体损伤为特征的各种疾病的方法。
更新日期:2021-10-12
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