Guan Xuejing, Qian Yingying, Shen Yue, Zhang Lulu, Du Yi, Dai Huili, Qian Jiaqi, Yan Yucheng
Department of Nephrology, Molecular Cell Lab for Kidney Disease, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Cell Physiol Biochem. 2015;36(1):285-98. doi: 10.1159/000374071. Epub 2015 May 4.
BACKGROUND/AIMS: Autophagy is a dynamic catabolic process that maintains cellular homeostasis. Whether it plays a role in promoting cell survival or cell death in the process of renal ischemia/reperfusion (I/R) remains controversial, partly because renal autophagy is usually examined at a certain time point. Therefore, monitoring of the whole time course of autophagy and apoptosis may help better understand the role of autophagy in renal I/R.
Autophagy and apoptosis were detected after mice were subjected to bilateral renal ischemia followed by 0-h to 7-day reperfusion, exposure of TCMK-1 cells to 24-h hypoxia, and 2 to 24-h reoxygenation. The effect of autophagy on apoptosis was assessed in the presence of autophagy inhibitor 3-methyladenine (3-MA) and autophagy activator rapamycin.
Earlier than apoptosis, autophagy increased from 2-h reperfusion, reached the maximum at day 2, and then began declining from day 3 when renal damage had nearly recovered to normal. Exposure to 24-h hypoxia induced autophagy markedly, but it decreased drastically after 4 and 8-h reoxygenation, which was accompanied with increased cell apoptosis. Inhibition of autophagy with 3-MA increased the apoptosis of renal tubular cells during I/R in vivo and hypoxia/reoxygenation (H/R) in vitro. In contrast, activation of autophagy by rapamycin significantly alleviated renal tissue damage and tubular cell apoptosis in the two models.
Autophagy was induced in a time-dependent manner and occurred earlier than the onset of cell apoptosis as an early response that played a renoprotective role during renal I/R and cell H/R. Up-regulation of autophagy may prove to be a potential strategy for the treatment of acute kidney injury.
背景/目的：自噬是一种维持细胞内稳态的动态分解代谢过程。在肾脏缺血/再灌注（I/R）过程中，它是促进细胞存活还是导致细胞死亡仍存在争议，部分原因是肾脏自噬通常在某个时间点进行检测。因此，监测自噬和凋亡的整个时间进程可能有助于更好地理解自噬在肾脏I/R中的作用。
在小鼠双侧肾脏缺血后进行0小时至7天的再灌注、将TCMK-1细胞暴露于24小时缺氧以及2至24小时复氧后，检测自噬和凋亡。在存在自噬抑制剂3-甲基腺嘌呤（3-MA）和自噬激活剂雷帕霉素的情况下，评估自噬对凋亡的影响。
自噬比凋亡更早出现，从再灌注2小时开始增加，在第2天达到最大值，然后从第3天开始下降，此时肾脏损伤已基本恢复正常。暴露于24小时缺氧显著诱导自噬，但在复氧4小时和8小时后急剧下降，同时细胞凋亡增加。在体内I/R和体外缺氧/复氧（H/R）过程中，用3-MA抑制自噬会增加肾小管细胞的凋亡。相反，雷帕霉素激活自噬可显著减轻两种模型中的肾组织损伤和肾小管细胞凋亡。
自噬以时间依赖性方式被诱导，且比细胞凋亡的发生更早，作为一种早期反应，在肾脏I/R和细胞H/R过程中发挥肾脏保护作用。上调自噬可能被证明是治疗急性肾损伤的一种潜在策略。
