Severe sepsis, a major health problem worldwide, has become one of the leading causes of death in ICU patients. Further study on the pathogenesis and treatment of acute kidney injury (AKI) is of great significance to reduce high mortality rate of sepsis. In this study, the mechanism by which ubiquitin specific peptidase 10 (USP10) reduces sepsis-induced AKI was investigated. Ligation and perforation of cecum (CLP) was employed to establish C57BL/6 mouse models of sepsis. Hematoxylin-eosin (H&E) staining was performed to detect renal injury. The concentrations of serum creatinine (Cr), urea nitrogen (BUN) and cystatin C (Cys C) were determined using a QuantiChrom™ Urea Assay kit. RT-qPCR and western blot were conducted to assess the USP10 expression level. DHE staining was used to detect reactive oxygen species (ROS) levels. H2O2, MDA and SOD levels were assessed using corresponding colorimetric kits. Western blot was used to examine the expression levels of Bcl-2, Bax, cleaved caspase-3, Sirt6, Nrf2 and HO-1. MTT assay was used to determine cell viability, whereas TUNEL staining and flow cytometry were used to assess cell apoptosis. In this study, we found that USP10 was decreased in CLP-induced mouse renal tissues. We identified that USP10 alleviated renal dysfunction induced by CLP. Moreover, USP10 was found to reduce oxidative stress, and abated LPS-induced renal tubular epithelial cell injury and apoptosis. Finally, we discovered that USP10 promoted activation of the NRF2/HO-1 pathway through SIRT6 and attenuated LPS-induced renal tubular epithelial cell injury. This study found that USP10 activates the NRF2/ARE signaling through SIRT6. USP10 alleviates sepsis-induced renal dysfunction and reduces renal tubular epithelial cell apoptosis and oxidative stress.

中文翻译：

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USP10通过调节Sirt6介导的Nrf2/ARE信号通路减轻败血症引起的急性肾损伤

严重脓毒症是世界范围内的主要健康问题，已成为 ICU 患者死亡的主要原因之一。进一步研究急性肾损伤（AKI）的发病机制和治疗对降低脓毒症的高死亡率具有重要意义。在这项研究中，研究了泛素特异性肽酶 10 (USP10) 减少败血症诱导的 AKI 的机制。采用盲肠结扎穿孔法（CLP）建立 C57BL/6 小鼠脓毒症模型。进行苏木精-伊红 (H&E) 染色以检测肾损伤。使用 QuantiChrom™ 尿素检测试剂盒测定血清肌酐 (Cr)、尿素氮 (BUN) 和胱抑素 C (Cys C) 的浓度。进行 RT-qPCR 和蛋白质印迹以评估 USP10 表达水平。DHE染色用于检测活性氧（ROS）水平。过氧化氢，使用相应的比色试剂盒评估 MDA 和 SOD 水平。Western blot 用于检测 Bcl-2、Bax、cleaved caspase-3、Sirt6、Nrf2 和 HO-1 的表达水平。MTT测定用于确定细胞活力，而TUNEL染色和流式细胞术用于评估细胞凋亡。在这项研究中，我们发现 USP10 在 CLP 诱导的小鼠肾组织中降低。我们确定 USP10 减轻了 CLP 诱导的肾功能障碍。此外，发现 USP10 可减少氧化应激，并减轻 LPS 诱导的肾小管上皮细胞损伤和细胞凋亡。最后，我们发现 USP10 通过 SIRT6 促进 NRF2/HO-1 通路的激活并减轻 LPS 诱导的肾小管上皮细胞损伤。该研究发现 USP10 通过 SIRT6 激活 NRF2/ARE 信号。