Nrf2 activation protects the liver from ischemia/reperfusion injury in mice.
Nrf2 activation protects the liver from ischemia/reperfusion injury in mice.
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DOI：
10.1097/sla.0000000000000287
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发表时间：
2014-07
影响因子：
9
通讯作者：
Yamamoto Y
中科院分区：
文献类型：
--
作者：
Kudoh K;Uchinami H;Yoshioka M;Seki E;Yamamoto Y
探讨Nrf2在肝缺血再灌注（I/R）损伤发病机制中的作用。肝I/R损伤是肝手术后导致肝功能衰竭的严重并发症。nf - e2相关因子2 （Nrf2）是一种在保护细胞抗氧化应激中起关键作用的转录因子。因此，我们认为Nrf2激活可以保护肝脏免受I/R损伤。野生型（WT）和nrf2缺陷小鼠分别用15-脱氧-Δ12、14-前列腺素J2 （15d-PGJ2）或载药处理。随后，这些小鼠进行60分钟肝脏70%缺血后再灌注。采集肝脏和血液样本，评估肝损伤及mRNA表达情况。在肝I/R后，与WT肝脏相比，nrf2缺陷肝脏表现出组织损伤增强，GSTm1、NQO1和GCLc诱导受损，氧化还原状态紊乱，TNF-α mRNA表达加剧。15d-PGJ2通过增加GSTm1、NQO1和GCLc的表达，维持氧化还原状态，降低TNF-α诱导，保护WT小鼠肝脏免受I/R损伤。15d-PGJ2诱导的这些作用在Nrf2−/−小鼠的肝脏中未见，并且在Nrf2+/+小鼠中未被PPARγ拮抗剂消除，这表明15d-PGJ2的保护作用是由Nrf2依赖的抗氧化反应介导的。Nrf2在肝I/R损伤的发生机制中起着至关重要的作用，可能成为肝脏手术中预防肝I/R损伤的新的治疗靶点。
To investigate the role of Nrf2 in the pathogenesis of hepatic ischemia-reperfusion (I/R) injury. Hepatic I/R injury is a serious complication that leads to liver failure after liver surgery. NF-E2-related factor 2 (Nrf2) is a transcription factor that plays a critical role in protecting cells against oxidative stress. Therefore, it is suggested that Nrf2 activation protects the liver from I/R injury. Wild-type (WT) and Nrf2-deficient mice were treated with 15-deoxy-Δ12, 14-prostaglandin J2 (15d-PGJ2), or a vehicle. Subsequently, these mice were subjected to 60 min hepatic 70% ischemia followed by reperfusion. Liver and blood samples were collected to evaluate liver injury and mRNA expressions. After hepatic I/R, Nrf2-deficient livers exhibited enhanced tissue damage, impaired GSTm1, NQO1, and GCLc inductions, disturbed redox state, and aggravated TNF-α mRNA expression in comparison to WT livers. 15d-PGJ2 treatment protected the livers of WT mice from I/R injury via increased expressions of GSTm1, NQO1 and GCLc, maintained redox status, and decreased TNF-α induction. These effects induced by 15d-PGJ2 were not seen in the livers of Nrf2−/− mice and were not annulled by PPARγ antagonist in Nrf2+/+ mice, suggesting that the protective effect of 15d-PGJ2 is mediated by Nrf2-dependent antioxidant response. Nrf2 plays a critical role in the mechanism of hepatic I/R injury and would be a new therapeutic target for preventing hepatic I/R injury during liver surgery.