Wang Dan, Zhou Yugang, Yang Na, Liu Jingjing, Lu Li, Gao Zhao
School of Medicine, Wuhan University of Science and Technology, Wuhan, China; Department of Emergency and Intensive Care, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, Hubei, China.
Department of Emergency and Intensive Care, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, Hubei, China.
Cell Signal. 2025 Jul;131:111757. doi: 10.1016/j.cellsig.2025.111757. Epub 2025 Mar 20.
Acute kidney injury (AKI) remains a critical condition with substantial morbidity and mortality in hospitalized patients. Emerging research has underscored the protective role of SIRT6 in kidney diseases through diverse signaling pathways. Our current report aimed to elucidate the mechanisms by which SIRT6 mitigated the progression of AKI. Immunohistochemical and Oil Red O staining techniques were employed to assess the expression of SIRT6 and lipid metabolism in both AKI patients and AKI mice treated with UBCS039, a specific SIRT6 activator (30 mg/kg, i.p.). Kidney tissues from AKI mice were analyzed using LC-MS/MS to uncover SIRT6-related signaling pathways involved in AKI. Additionally, human proximal renal tubule cells (HK-2) were exposed to UBCS039 or transfected pcDNA3.1-SIRT6 overexpression plasmid to investigate the underlying signaling mechanisms of SIRT6 on lipid metabolism using Western blotting analysis and Oil Red O staining. Gene expression levels of ACMSD was detected by qRT-PCR and Western blotting in HK-2 cells. Dual-luciferase reporter assay was used to verify the effect of SIRT6 on regulating ACMSD transcription. Our findings revealed a significant reduction in SIRT6 expression in both AKI patients and AKI mice. Treatment with UBCS039, however, significantly decreased lipid accumulation and apoptosis in AKI mice. Proteomic analysis and Dual-luciferase reporter assay identified ACMSD as a downstream target of SIRT6. In vitro studies further demonstrated that SIRT6 enhanced lipid metabolism and mitigated apoptosis through the inhibition of ACMSD expression. This study demonstrated that SIRT6 promoted lipid metabolism by inhibiting the ACMSD pathway, thereby reducing apoptosis in AKI. These findings suggested that targeting ACMSD could offer a novel therapeutic strategy for SIRT6-mediated intervention in AKI.
急性肾损伤（AKI）在住院患者中仍然是一种具有高发病率和死亡率的危急病症。新出现的研究强调了SIRT6通过多种信号通路在肾脏疾病中的保护作用。我们目前的报告旨在阐明SIRT6减轻AKI进展的机制。采用免疫组织化学和油红O染色技术评估SIRT6的表达以及用特异性SIRT6激活剂UBCS039（30mg/kg，腹腔注射）治疗的AKI患者和AKI小鼠的脂质代谢情况。使用液相色谱-串联质谱法（LC-MS/MS）分析AKI小鼠的肾组织，以揭示参与AKI的SIRT6相关信号通路。此外，将人近端肾小管细胞（HK-2）暴露于UBCS039或转染pcDNA3.1-SIRT6过表达质粒，通过蛋白质印迹分析和油红O染色研究SIRT6对脂质代谢的潜在信号机制。通过qRT-PCR和蛋白质印迹法检测HK-2细胞中ACMSD的基因表达水平。使用双荧光素酶报告基因检测法验证SIRT6对调节ACMSD转录的作用。我们的研究结果显示，AKI患者和AKI小鼠的SIRT6表达均显著降低。然而，用UBCS039治疗可显著减少AKI小鼠的脂质积累和细胞凋亡。蛋白质组学分析和双荧光素酶报告基因检测法确定ACMSD为SIRT6的下游靶点。体外研究进一步表明，SIRT6通过抑制ACMSD表达增强脂质代谢并减轻细胞凋亡。本研究表明，SIRT6通过抑制ACMSD途径促进脂质代谢，从而减少AKI中的细胞凋亡。这些发现提示，靶向ACMSD可能为SIRT6介导的AKI干预提供一种新的治疗策略。
