Key Laboratory of Molecular Target & Clinical Pharmacology and the State & NMPA Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, PR China.
School of Pharmacy, Nantong University, 19 Qixiu Road, Nantong, Jiangsu 226001, PR China.
Phytomedicine. 2022 Jul;101:154122. doi: 10.1016/j.phymed.2022.154122. Epub 2022 Apr 21.
Acute kidney injury (AKI), a common multidisciplinary diagnostic clinical critical illness, eventually causes end-stage renal disease (ESRD). Although many clinical measures have been taken to prevent or treat AKI, high morbidity and death rates were recorded. Therefore, in-depth pathogenesis study and search for new therapeutic targets are in demand. Interestingly, the suirtuins family showed a significant protective effect in AKI. Sirtuins (SIRT1-7) is a family of seven proteins with NAD-dependent type III histone deacetylase activity. Sirtuins family members were involved by AKI, and regulation of sirtuins activities significantly improved AKI-induced renal injury. Therefore, the therapeutic role and molecular mechanisms of the sirtuins family in AKI has important research implications for clinical applications or basic research.
This review summarizes recent advances in the roles and functions of the sirtuins family, discusses their therapeutic effects on AKI and related molecular mechanisms, and the mechanisms of action of small molecule specific activators or inhibitors sirtuins in the prevention and treatment of AKI were discussed.
The data in this review were retrieved from various scientific databases (PubMed, Google scholar, Science Direct, and Web of Science), till December 2021. The keywords were used as follows: "Sirtuins", "Acute kidney injury", "AKI", "Sirtuins modulators" and "Histone deacetylation". The retrieved data followed PRISMA criteria (preferred reporting items for systematic review).
Growing evidence indicates that members of the sirtuins family regulate the development and progression of different renal diseases, including AKI, through anti-inflammation, antioxidation, anti-apoptotic, and maintenance of mitochondrial homeostasis. The molecular mechanism of Sirtuins family on AKI mainly regulated NF-κB, JNK/ERK, and AMPK/mTOR signaling pathways, upregulated the expression of PGC-1α, HO-1, NRF2, Bcl-2, OPA1, and AMPK, and downregulated the expression of NRLP3, IL-1β, TNF-α, IL-6, ROS, MFF, Drp1, Bax, ERK, and mTOR. In addition, the active ingredients of herbs (resveratrol, thujaplicins, huperzine, and curcumin) could activate the activity of SIRT1 or SIRT3, thereby improving AKI. Meanwhile, the synthetic Sirtuins inhibitor (AK-1) inhibited SIRT2 activity, thus alleviating AKI. In the future, more specific modulators will remain needed to enhance the clinical therapeutic role of the Sirtuins family in AKI.
The sirtuins family is a promising type III histone deacetylase for AKI treatment. This review will provide insight into sirtuins family's therapeutic role in AKI and promote the clinical use of sirtuins modulators in AKI.
急性肾损伤（AKI）是一种常见的多学科诊断性临床危重症，最终导致终末期肾病（ESRD）。尽管采取了许多临床措施来预防或治疗 AKI，但仍有很高的发病率和死亡率。因此，深入研究发病机制和寻找新的治疗靶点是当务之急。有趣的是，沉默调节蛋白（sirtuins）家族在 AKI 中显示出显著的保护作用。沉默调节蛋白（SIRT1-7）是一类具有 NAD 依赖性 III 型组蛋白去乙酰化酶活性的七种蛋白质家族。沉默调节蛋白家族成员参与 AKI 的发生，调节沉默调节蛋白的活性可显著改善 AKI 诱导的肾损伤。因此，沉默调节蛋白家族在 AKI 中的治疗作用和分子机制对临床应用或基础研究具有重要的研究意义。
本综述总结了沉默调节蛋白家族的作用和功能的最新进展，讨论了它们在 AKI 中的治疗作用及相关分子机制，以及小分子特异性激活剂或抑制剂沉默调节蛋白在 AKI 预防和治疗中的作用机制。
本综述中的数据来自各种科学数据库（PubMed、Google Scholar、Science Direct 和 Web of Science），检索时间截至 2021 年 12 月。使用的关键词如下：“沉默调节蛋白”、“急性肾损伤”、“AKI”、“沉默调节蛋白调节剂”和“组蛋白去乙酰化”。检索到的数据遵循 PRISMA 标准（系统评价的首选报告项目）。
越来越多的证据表明，沉默调节蛋白家族的成员通过抗炎、抗氧化、抗凋亡和维持线粒体稳态来调节不同肾脏疾病（包括 AKI）的发生和进展。沉默调节蛋白家族对 AKI 的分子机制主要通过 NF-κB、JNK/ERK 和 AMPK/mTOR 信号通路进行调节，上调 PGC-1α、HO-1、NRF2、Bcl-2、OPA1 和 AMPK 的表达，下调 NRLP3、IL-1β、TNF-α、IL-6、ROS、MFF、Drp1、Bax、ERK 和 mTOR 的表达。此外，草药的活性成分（白藜芦醇、土木香内酯、石杉碱甲和姜黄素）可激活 SIRT1 或 SIRT3 的活性，从而改善 AKI。同时，合成的沉默调节蛋白抑制剂（AK-1）抑制 SIRT2 活性，从而缓解 AKI。在未来，仍需要更具特异性的调节剂来增强沉默调节蛋白家族在 AKI 中的临床治疗作用。
沉默调节蛋白家族是 AKI 治疗的一种有前途的 III 型组蛋白去乙酰化酶。本综述将为沉默调节蛋白家族在 AKI 中的治疗作用提供新的见解，并促进沉默调节蛋白调节剂在 AKI 中的临床应用。
