Negative feedback loop of autophagy and endoplasmic reticulum stress in rapamycin protection against renal ischemia‐reperfusion injury during initial reperfusion phase-猫眼课题宝

DOI：

10.1096/fj.201800299r

发表时间：

2018-05

期刊：

The FASEB Journal

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

Xinyuan Li;Gongmin Zhu;X. Gou;Weiyang He;Hubin Yin;Xiaoyu Yang;J. Li

雷帕霉素是一种免疫抑制剂，广泛用于肾移植患者。然而，雷帕霉素的治疗效果仍有争议。此外，先前的研究表明，雷帕霉素的有害作用主要发生在给药≥24小时时。然而，很少有研究关注仅在初始再灌注阶段给药雷帕霉素的短期影响。因此，我们设计了这项研究，以探索雷帕霉素在初始再灌注阶段（24小时内）在灌注物中混合雷帕霉素的特定治疗方案下的潜在作用和机制。有趣的是，我们发现雷帕霉素在体内和体外的初始再灌注阶段，特别是在再灌注后8小时，维持肾功能并减轻缺血再灌注（I/R）诱导的细胞凋亡。同时，雷帕霉素激活自噬，抑制内质网应激和3条展开蛋白反应途径：ATF6、PERK和IRE1α。有趣的是，我们进一步发现，当自噬被氯喹和3‐甲基腺嘌呤抑制或当内质网应激被thapsigargin诱导时，雷帕霉素的保护作用被抑制。此外，就雷帕霉素的调节作用而言，自噬与内质网应激之间存在负反馈回路，在肾I/R损伤的初始再灌注阶段，自噬抑制内质网应激，内质网应激增加促进自噬。我们的研究证明，在初始再灌注阶段用雷帕霉素立即再灌注可以修复肾功能，并通过激活自噬来减少细胞凋亡，从而进一步抑制内质网应激。这些结果提示在肾移植引起的肾I/R损伤的初始再灌注阶段应用一种新的治疗方式。朱李津,X。,G。,郭台铭,X。,他,W,阴,H,杨,X。,j .负反馈循环自噬和内质网应激的雷帕霉素预防肾缺血再灌注损伤在初始再灌注阶段。[32](2018): 6002-6018。www.fasebj.org

Rapamycin, an immunosuppressant, is widely used in patients with kidney transplant. However, the therapeutic effects of rapamycin remain controversial. Additionally, previous studies have revealed deleterious effects of rapamycin predominantly when administered for ≥24 h. Few studies, however, have focused on the short term effects of rapamycin administered only during the initial reperfusion phase. As such, we designed this study to explore the potential effects and mechanisms of rapamycin under a specific therapeutic regimen in which rapamycin is mixed in the perfusate during the initial reperfusion phase (within 24 h). Interestingly, we found that rapamycin maintained renal function and attenuated ischemia‐reperfusion (I/R)‐induced apoptosis in vivo and in vitro during the initial reperfusion phase, especially at 8 h after reperfusion. Simultaneously, rapamycin activated autophagy and inhibited endoplasmic reticulum (ER) stress and 3 pathways of unfolding protein response: ATF6, PERK, and IRE1α. Interestingly, we further found that the protective effects of rapamycin were suppressed when autophagy was inhibited by chloroquine and 3‐methyladenine or when ER stress was induced by thapsigargin. Moreover, in terms of the regulatory effects of rapamycin, a negative‐feedback loop between autophagy and ER stress occurred, with autophagy inhibiting ER stress and increased ER stress promoting autophagy during the initial reperfusion phase of renal I/R injury. Our study provides evidence that immediate reperfusion with rapamycin during the initial reperfusion phase repairs renal function and reduces apoptosis via activating autophagy, which could further inhibit ER stress. These results suggest a novel treatment modality for application during the initial reperfusion phase of renal I/R injury caused by kidney transplantation.—Li, X., Zhu, G., Gou, X., He, W., Yin, H., Yang, X., Li, J. Negative feedback loop of autophagy and endoplasmic reticulum stress in rapamycin protection against renal ischemia‐reperfusion injury during initial reperfusion phase. 32, 6002–6018 (2018). www.fasebj.org

Negative feedback loop of autophagy and endoplasmic reticulum stress in rapamycin protection against renal ischemia‐reperfusion injury during initial reperfusion phase

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