Augmenter of liver regeneration protects the kidney from ischaemia-reperfusion injury in ferroptosis
Augmenter of liver regeneration protects the kidney from ischaemia-reperfusion injury in ferroptosis
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DOI：
10.1111/jcmm.14302
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发表时间：
2019-06-01
影响因子：
5.3
通讯作者：
Zhang, Ling
中科院分区：
文献类型：
--
作者：
Huang, Li-li;Liao, Xiao-hui;Zhang, Ling
急性肾损伤（阿基）是一种常见的严重的临床疾病，具有较高的发病率和死亡率。缺血再灌注（I/R）损伤仍然是临床上阿基的主要原因。铁凋亡是最近发现的一种程序性细胞死亡（PCD）形式，其特征在于铁依赖性活性氧（ROS）积累。令人信服的证据表明，肾小管细胞死亡涉及铁凋亡，但潜在的机制仍不清楚。肝再生增强因子（Augmenter of Liver Regeneration，ALR）是一种广泛分布的多功能蛋白，在多种组织中均有表达。我们前期的研究表明ALR具有抗氧化功能。然而，ALR的调节机制仍不清楚，需要进一步研究。在此，为了阐明ALR在铁凋亡中的作用，在I/R诱导的阿基的体外模型中使用短发夹RNA慢病毒（shRNA）抑制ALR表达。结果表明，铁凋亡水平增加，特别是在shRNA/ALR组中，伴随着增加的ROS和线粒体损伤。此外，用erastin抑制系统xc-可抑制铁凋亡，特别是ALR表达的沉默。出乎意料的是，我们展示了一个新的信号通路的ferroptosis。总之，我们首次在体外I/R模型中发现ALR沉默可导致铁凋亡。值得注意的是，我们表明，I/R诱导的肾脏铁凋亡是由ALR介导的，ALR与谷胱甘肽-谷胱甘肽过氧化物酶（GSH-GPx）系统有关。
Acute kidney injury (AKI) is a common and severe clinical condition with high morbidity and mortality. Ischaemia-reperfusion (I/R) injury remains the major cause of AKI in the clinic. Ferroptosis is a recently discovered form of programmed cell death (PCD) that is characterized by iron-dependent accumulation of reactive oxygen species (ROS). Compelling evidence has shown that renal tubular cell death involves ferroptosis, although the underlying mechanisms remain unclear. Augmenter of liver regeneration (ALR) is a widely distributed multifunctional protein that is expressed in many tissues. Our previous study demonstrated that ALR possesses an anti-oxidant function. However, the modulatory mechanism of ALR remains unclear and warrants further investigation. Here, to elucidate the role of ALR in ferroptosis, ALR expression was inhibited using short hairpin RNA lentivirals (shRNA) in vitro model of I/R-induced AKI. The results suggest that the level of ferroptosis is increased, particularly in the shRNA/ALR group, accompanied by increased ROS and mitochondria) damage. Furthermore, inhibition of system xc- with erastin aggravates ferroptosis, particularly silencing of the expression of ALR. Unexpectedly, we demonstrate a novel signalling pathway of ferroptosis. In summary, we show for the first time that silencing ALR aggravates ferroptosis in an in vitro model of I/R. Notably, we show that I/R induced kidney ferroptosis is mediated by ALR, which is linked to the glutathione-glutathione peroxidase (GSH-GPx) system.