Department of Critical Care Medicine, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
Department of Critical Care Medicine, Union Jiangbei Hospital, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
Am J Physiol Renal Physiol. 2024 Jul 1;327(1):F184-F197. doi: 10.1152/ajprenal.00337.2023. Epub 2024 May 23.
Zn levels are reported to be correlated with kidney function. We explored the significance of Zn in sepsis-induced acute kidney injury (SI-AKI) through the regulation of sirtuin 7 (SIRT7) activity. The sepsis rat model was established by cecal ligation and perforation (CLP) and intraperitoneally injected with ZnSO or SIRT7 inhibitor 97491 (SIRT7i), with renal tubular injury assessed by hematoxylin and eosin staining. In vitro, human renal tubular epithelial cells (HK-2) were induced with lipopolysaccharide to obtain a renal injury cell model, followed by ZnSO or SIRT7i and autophagy inhibitor (3-methyladenine) treatment. Interleukin (IL)-1β, IL-18, reactive oxygen species (ROS), Parkin acetylation level, kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) expression levels were determined. The renal tubule injury, inflammation condition, and pyroptosis-related and autophagy-related protein levels were assessed. The pyroptosis in kidney tissues and autophagosome formation were observed by transmission electron microscopy. Zn alleviated renal injury in CLP rats and inhibited pyroptosis and its related protein levels by inhibiting SIRT7 activity in septic rat renal tissues. In vitro, Zn increased HK-2 cell viability and reduced KIM-1, NGAL, IL-1β, IL-18, NLRP3 inflammasome, cleaved caspase-1, gasdermin D-N levels, and pyroptotic cell number. Zn increased autophagosome number and LC3BII/LC3BI ratio and decreased TOM20, TIM23, P62, and mitochondrial ROS levels. Zn increased Parkin acetylation by repressing SIRT7 activity. Inhibiting mitophagy partially averted Zn-inhibited NLRP3 inflammasome activation and apoptosis in HK-2 cells. Zn upregulated Parkin acetylation by repressing SIRT7 activity to promote mitophagy and inhibit NLRP3 inflammasome activation and pyroptosis, thus improving SI-AKI. Zn upregulated Parkin acetylation by repressing sirtuin 7 activity to promote mitophagy and inhibit NLRP3 inflammasome activation and pyroptosis, thus improving sepsis-induced acute kidney injury.
锌水平与肾功能相关。我们通过调节 SIRT7 活性来探讨锌在脓毒症诱导的急性肾损伤（SI-AKI）中的意义。通过盲肠结扎穿孔（CLP）建立脓毒症大鼠模型，并腹腔内注射 ZnSO4 或 SIRT7 抑制剂 97491（SIRT7i），通过苏木精和伊红染色评估肾小管损伤。在体外，用脂多糖诱导人肾小管上皮细胞（HK-2）获得肾损伤细胞模型，然后用 ZnSO4 或 SIRT7i 和自噬抑制剂（3-甲基腺嘌呤）处理。测定白细胞介素（IL）-1β、IL-18、活性氧（ROS）、Parkin 乙酰化水平、肾损伤分子-1（KIM-1）和中性粒细胞明胶酶相关脂质运载蛋白（NGAL）的表达水平。评估肾小管损伤、炎症状态、以及与细胞焦亡和自噬相关的蛋白水平。通过透射电子显微镜观察肾组织细胞焦亡和自噬小体形成。Zn 通过抑制 SIRT7 活性减轻 CLP 大鼠的肾损伤，并抑制脓毒症大鼠肾组织的细胞焦亡及其相关蛋白水平。在体外，Zn 增加 HK-2 细胞活力，降低 KIM-1、NGAL、IL-1β、IL-18、NLRP3 炎性体、裂解半胱氨酸天冬氨酸蛋白酶-1、gasdermin D-N 水平和细胞焦亡细胞数量。Zn 增加自噬小体数量和 LC3BII/LC3BI 比值，并降低 TOM20、TIM23、P62 和线粒体 ROS 水平。Zn 通过抑制 SIRT7 活性增加 Parkin 乙酰化。抑制线粒体自噬部分逆转了 Zn 抑制的 HK-2 细胞 NLRP3 炎性体激活和凋亡。Zn 通过抑制 SIRT7 活性上调 Parkin 乙酰化，促进线粒体自噬，抑制 NLRP3 炎性体激活和细胞焦亡，从而改善 SI-AKI。
