Rapamycin induces autophagy to alleviate acute kidney injury following cerebral ischemia and reperfusion via the mTORC1/ATG13/ULK1 signaling pathway.
Rapamycin induces autophagy to alleviate acute kidney injury following cerebral ischemia and reperfusion via the mTORC1/ATG13/ULK1 signaling pathway.
复制标题
雷帕霉素通过 mTORC1/ATG13/ULK1 信号通路诱导自噬减轻脑缺血再灌注后的急性肾损伤
DOI：
10.3892/mmr.2018.9586
复制
发表时间：
2018-12
影响因子：
3.4
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Su Y;Lu J;Gong P;Chen X;Liang C;Zhang J
急性肾损伤（阿基）是临床上常见的缺血再灌注（I/R）的严重并发症，与高发病率和死亡率以及住院时间延长相关。雷帕霉素是一种大环内酯类药物，主要用于器官移植后的抗排斥治疗和自身免疫性疾病的治疗。雷帕霉素作为一种自噬诱导剂，已被鉴定为对肾I/R诱导的阿基发挥保护作用。然而，雷帕霉素预处理是否可以减轻脑I/R（CIR）后的阿基仍有待充分阐明。本研究的目的是研究CIR对大鼠肾脏系统的影响以及雷帕霉素在CIR后阿基中的作用。在本研究中，在Sprague-Dawley大鼠中通过90分钟的大脑中动脉闭塞和24小时的再灌注建立CIR模型，并在CIR之前腹腔注射雷帕霉素（剂量：1 mg/kg; 0.5 h）进行预处理。随后测定血清肌酐和血尿素氮（BUN）水平，以及炎症、凋亡和自噬相关标志物的表达。除肾脏的某些组织病理学改变外，还发现CIR显著增加血清肌酐、BUN、肿瘤坏死因子-α和白细胞介素-1 β的水平，并显著诱导细胞凋亡和自噬。观察到雷帕霉素通过哺乳动物靶向雷帕霉素复合物1/自噬相关的13/unc-51样自噬激活激酶1信号通路诱导自噬，并且雷帕霉素预处理显著改善CIR后大鼠的肾功能，减轻肾组织炎症和细胞凋亡。总之，结果表明，雷帕霉素可以通过诱导自噬来减轻CIR后的阿基。
Acute kidney injury (AKI) is a clinically common and severe complication of ischemia-reperfusion (I/R), associated with high morbidity and mortality rates, and prolonged hospitalization. Rapamycin is a type of macrolide, primarily used for anti-rejection therapy following organ transplantation and the treatment of autoimmune diseases. Rapamycin has been identified to exert a protective effect against AKI induced by renal I/R as an autophagy inducer. However, whether rapamycin preconditioning may relieve AKI following cerebral I/R (CIR) remains to be fully elucidated. The purpose of the present study was to investigate the effects of CIR on the renal system of rats and the role of rapamycin in AKI following CIR. In the present study, a CIR model was established in Sprague-Dawley rats via a 90-min period of middle cerebral artery occlusion and 24 h reperfusion, and pretreatment with an intraperitoneal injection of rapamycin (dosage: 1 mg/kg; 0.5 h) prior to CIR. The levels of serum creatinine and blood urea nitrogen (BUN), and the expression of inflammation-, apoptosis- and autophagy-associated markers were subsequently measured. In addition to certain histopathological alterations to the kidney, it was identified that CIR significantly increased the levels of serum creatinine, BUN, tumor necrosis factor-α and interleukin-1β, and significantly induced apoptosis and autophagy. It was observed that rapamycin induced autophagy through the mammalian target of rapamycin complex 1/autophagy-related 13/unc-51 like autophagy activating kinase 1 signaling pathway, and that rapamycin pre-treatment significantly improved renal function and alleviated renal tissue inflammation and cell apoptosis in rats following CIR. In conclusion, the results suggested that rapamycin may alleviate AKI following CIR via the induction of autophagy.