Zhao Wenyu, Zhang Lei, Chen Rui, Lu Hanlan, Sui Mingxing, Zhu Youhua, Zeng Li
Department of Organ Transplantation, Changhai Hospital, Second Military Medical University, Shanghai, China.
Front Physiol. 2018 Nov 14;9:1526. doi: 10.3389/fphys.2018.01526. eCollection 2018.
Acute kidney injury (AKI), which involves the loss of kidney function caused by damage to renal tubular cells, is an important public health concern. We previously showed that sirtuin (SIRT)3 protects the kidneys against mitochondrial damage by inhibiting the nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome, attenuating oxidative stress, and downregulating proinflammatory cytokines. In this article, we investigated the role of autophagy, mediated by a mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK), in the protective effect of SIRT3, against sepsis-induced AKI, in a mouse model of cecal ligation and puncture (CLP). The AKI in CLP mice was associated with the upregulation of autophagy markers; this effect was abolished in SIRT3 mice in parallel with the downregulation of phospho (p)-AMPK and the upregulation of p-mTOR. Pretreatment with the autophagy inhibitor 3-methyladenine (3-MA) or AMPK inhibitor compound isotonic saline (C), exacerbated AKI. SIRT3 overexpression promoted autophagy, upregulated p-AMPK and downregulated p-mTOR in CLP mice, attenuating sepsis-induced AKI, tubular cell apoptosis, and inflammatory cytokine accumulation in the kidneys. The blockage of autophagy induction largely abolished the protective effect of SIRT3 in sepsis-induced AKI. These findings indicate that SIRT3 protects against CLP-induced AKI by inducing autophagy through regulation of the AMPK/mTOR pathway.
急性肾损伤（AKI）涉及肾小管细胞损伤导致的肾功能丧失，是一个重要的公共卫生问题。我们之前表明，沉默调节蛋白（SIRT）3通过抑制核苷酸结合寡聚化结构域（NOD）样受体蛋白3（NLRP3）炎性小体、减轻氧化应激和下调促炎细胞因子来保护肾脏免受线粒体损伤。在本文中，我们在盲肠结扎和穿刺（CLP）小鼠模型中研究了由雷帕霉素靶蛋白（mTOR）和AMP活化蛋白激酶（AMPK）介导的自噬在SIRT3对脓毒症诱导的AKI的保护作用中的作用。CLP小鼠的AKI与自噬标志物的上调有关；在SIRT3小鼠中这种作用被消除，同时磷酸化（p）-AMPK下调，p-mTOR上调。用自噬抑制剂3-甲基腺嘌呤（3-MA）或AMPK抑制剂复方等渗盐水（C）预处理会加重AKI。SIRT3过表达促进CLP小鼠的自噬，上调p-AMPK并下调p-mTOR，减轻脓毒症诱导的AKI、肾小管细胞凋亡和肾脏中炎性细胞因子的积累。自噬诱导的阻断在很大程度上消除了SIRT3在脓毒症诱导的AKI中的保护作用。这些发现表明，SIRT3通过调节AMPK/mTOR途径诱导自噬来保护免受CLP诱导的AKI。
