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《天津医科大学学报》[ISSN:1006-8147/CN:12-1259/R]

卷:

31卷

期数:

2025年03期

页码:

237-242

栏目:

基础医学

出版日期:

2025-05-20

文章信息/Info

Title:

Study of the effect and mechanism of Imeglimin，a novel hypoglycemic drug，on the palmitic acid-induced renal tubular epithelial cell injury

文章编号:

1006-8147(2025)03-0237-06

作者:

润雅杰¹; 2; 苏瑞³; 牛文彦¹

（1.天津医科大学基础医学院免疫学系，天津300070；2.天津医科大学医学技术学院，天津 300203；3.天津市第二人民医院，天津市肝病医学研究所，天津300192）

Author(s):

RUN Yajie¹; 2; SU Rui³; NIU Wenyan¹

（1.Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China; 2.School of Medical Technology, Tianjin Medical University, Tianjin 300203, China; 3.Tianjin Institute of Hepatology, Tianjin Second People’s Hospital, Tianjin 300192, China）

关键词:

降糖药物; 肾小管上皮细胞; 棕榈酸; 腺苷酸活化蛋白激酶

Keywords:

hypoglycemic drug; renal tubular epithelial cell; palmitic acid; AMP-activated protein kinase

分类号:

R392.1

DOI:

10.20135/j.issn.1006-8147.2025.03.0237

文献标志码:

A

摘要:

目的：探讨新型降糖药伊美格列明（Imeglimin）对棕榈酸（PA）诱导的HK-2肾小管上皮细胞脂毒性损伤的影响及机制。方法：CCK-8实验确定PA或Imeglimin的实验浓度；将HK-2细胞分为BSA组（对照组）、PA组和PA+Imeglimin组（治疗组）。油红O染色检测细胞脂滴；免疫印迹检测固醇调节元件结合蛋白-1（SREBP-1）的核转位、c-Jun氨基末端激酶（JNK）、核因子κB（NF-κB）和腺苷酸活化蛋白激酶（AMPK）的磷酸化、沉默调节蛋白1（Sirt1）、过氧化物酶体增殖物激活受体γ共激活因子-1α（PGC-1α）和沉默调节蛋白3（Sirt3）的蛋白水平；RT-qPCR检测脂肪酸合酶（FAS）和硬脂酰辅酶A去饱和酶（SCD1）的mRNA水平；试剂盒检测细胞内活性氧簇（ROS）生成、丙二醛（MDA）含量和超氧化物歧化酶（SOD）活性。结果：选用300 μmol/L PA和100 μmol/L Imeglimin进行实验。与对照组相比，PA组细胞内形成大量脂滴，SREBP-1的核转位水平与FAS和SCD1的mRNA转录水平显著升高（t=4.72、10.81、28.30、22.65，均P<0.01）；JNK和NF-κB的磷酸化水平显著升高（t=23.66、18.78，均P<0.000 1）；细胞内ROS显著增加，MDA含量显著升高（t=5.54，P<0.01），SOD活性显著降低（t=10.74，P<0.000 1）；p-AMPK/AMPK、Sirt1、PGC-1α、Sirt3的蛋白水平显著降低（t=5.40、12.02、25.97、8.67，均P<0.01）。与PA组相比，治疗组细胞内脂滴显著减少，SREBP-1的核转位水平与FAS和SCD1的mRNA转录水平显著降低（t=3.53、11.24、15.39、18.33，均P<0.05），JNK和NF-κB的磷酸化水平显著降低（t=12.25、18.43，均P<0.001），细胞内ROS显著减少，MDA含量显著降低（t=4.22，P<0.01），SOD活性显著升高（t=6.84，P<0.001），p-AMPK/AMPK、Sirt1、PGC-1α、Sirt3的蛋白水平显著升高（t=5.87、7.96、11.77、6.14，均P<0.01）。结论：Imeglimin可能通过AMPK/Sirt1/PGC-1α/Sirt3信号通路改善PA诱导的HK-2肾小管上皮细胞的脂毒性损伤。

Abstract:

Objective： To investigate the effect and mechanism of Imeglimin，a novel hypoglycemic drug，on palmitic acid （PA）-induced lipotoxicity injury in HK-2 renal tubular epithelial cells. Methods：The cell counting Kit-8 （CCK-8） was used to determine the experimental concentrations of PA or Imeglimin. HK-2 cells were divided into BSA group （control group），PA group，PA+Imeglimin group （treatment group），respectively. Oil red O staining was used to detect cell lipid droplets. Western blotting was used to detect the nuclear translocation of sterol regulatory element binding protein-1 （SREBP-1），the phosphorylation of c-Jun amino terminal kinase （JNK），nuclear factor κB （NF-κB） and AMP-activated protein kinase （AMPK），the protein levels of sirtuin 1 （Sirt1），peroxisome proliferator-activated receptor γ coactivator-1α （PGC-1α） and sirtuin 3 （Sirt3）. The RT-qPCR was used to detect the mRNA levels of fatty acid synthase （FAS） and stearoyl-CoA desaturase 1 （SCD1）. The corresponding kits were used to detect reactive oxygen species （ROS） generation，malondialdehyde （MDA） content and superoxide dismutase （SOD） activity. Results：300 μmol/L PA and 100 μmol/L Imeglimin were selected as the subsequent experimental concentrations. Compared with control group，a large number of lipid droplets were formed in the HK-2 cells，the nuclear translocation level of SREBP-1 and the mRNA transcription levels of FAS and SCD1 were significantly increased （t=4.72，10.81，28.30，22.65，all P<0.01），the phosphorylation levels of JNK and NF-κB were significantly increased （t=23.66，18.78，both P<0.000 1），intracellular ROS level was significantly increased，MDA content was significantly increased （t=5.54，P<0.01），SOD activity was significantly decreased （t=10.74，P<0.000 1），and the protein levels of p-AMPK/AMPK，Sirt1，PGC-1α and Sirt3 were significantly decreased （t=5.40，12.02，25.97，8.67，all P<0.01） in PA group. Compared with PA group，intracellular lipid droplets were significantly decreased，nuclear translocation level of SREBP-1 and mRNA transcription levels of FAS and SCD1 were sig-nificantly decreased （t=3.53，11.24，15.39，18.33，all P<0.05），the phosphorylation levels of JNK and NF-κB were significantly decreased （t=12.25，18.43，both P<0.001），intracellular ROS level was significantly decreased，MDA content was significantly decreased （t=4.22，P<0.01），SOD activity was significantly increased （t=6.84，P<0.001），and the protein levels of p-AMPK/AMPK，Sirt1，PGC-1α and Sirt3 were significantly increased （t=5.87，7.96，11.77，6.14，all P<0.01） in treatment group. Conclusion：Imeglimin may improve the PA-induced lipotoxicity injury in HK-2 renal tubular epithelial cells through AMPK/Sirt1/PGC-1α/Sirt3 signaling pathway.

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备注/Memo

备注/Memo:

基金项目: 国家自然科学基金面上项目（81870547，82270856）
作者简介: 润雅杰（1999-），女，硕士在读，研究方向：医学检验技术；
通信作者：牛文彦，E-mail：wniu@tmu.edu.cn。

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更新日期/Last Update: 2025-06-01