Laboratory of Abdominal Transplantation, Transplantation Research Group, Department of Microbiology and Immunology, KU Leuven, B-3000 Leuven, Belgium.
Department of Abdominal Transplant Surgery, University Hospitals Leuven, B-3000 Leuven, Belgium.
Int J Mol Sci. 2020 Sep 29;21(19):7185. doi: 10.3390/ijms21197185.
Renal ischemia-reperfusion (IR) injury leading to cell death is a major cause of acute kidney injury, contributing to morbidity and mortality. Autophagy counteracts cell death by removing damaged macromolecules and organelles, making it an interesting anchor point for treatment strategies. However, autophagy is also suggested to enhance cell death when the ischemic burden is too strong. To investigate whether the role of autophagy depends on the severity of ischemic stress, we analyzed the dynamics of autophagy and apoptosis in an IR rat model with mild (45 min) or severe (60 min) renal ischemia. Following mild IR, renal injury was associated with reduced autophagy, enhanced mammalian target of rapamycin (mTOR) activity, and apoptosis. Severe IR, on the other hand, was associated with a higher autophagic activity, independent of mTOR, and without affecting apoptosis. Autophagy stimulation by trehalose injected 24 and 48 h prior to onset of severe ischemia did not reduce renal injury markers nor function, but reduced apoptosis and restored tubular dilation 7 days post reperfusion. This suggests that trehalose-dependent autophagy stimulation enhances tissue repair following an IR injury. Our data show that autophagy dynamics are strongly dependent on the severity of IR and that trehalose shows the potential to trigger autophagy-dependent repair processes following renal IR injury.
肾缺血再灌注（IR）损伤导致细胞死亡是急性肾损伤的主要原因，导致发病率和死亡率增加。自噬通过清除受损的大分子和细胞器来抵抗细胞死亡，使其成为治疗策略的一个有趣的切入点。然而，当缺血负担过重时，自噬也被认为会增强细胞死亡。为了研究自噬的作用是否取决于缺血应激的严重程度，我们分析了轻度（45 分钟）或重度（60 分钟）肾缺血的 IR 大鼠模型中自噬和细胞凋亡的动态变化。轻度 IR 后，肾损伤与自噬减少、哺乳动物雷帕霉素靶蛋白（mTOR）活性增强和细胞凋亡有关。另一方面，严重的 IR 与更高的自噬活性相关，与 mTOR 无关，并且不影响细胞凋亡。在严重缺血开始前 24 小时和 48 小时注射海藻糖刺激自噬，并未减轻肾损伤标志物或功能，但减少了细胞凋亡并在再灌注后 7 天恢复了管状扩张。这表明海藻糖依赖性自噬刺激增强了 IR 损伤后的组织修复。我们的数据表明，自噬动力学强烈依赖于 IR 的严重程度，并且海藻糖具有在肾 IR 损伤后触发自噬依赖性修复过程的潜力。
