文章摘要
王向晶,周奕菁,黄科,等.参芪地黄汤通过GPX4信号通路调控糖尿病肾病小鼠铁死亡的机制研究[J].浙江中医药大学学报,2024,48(4):407-415.
参芪地黄汤通过GPX4信号通路调控糖尿病肾病小鼠铁死亡的机制研究
Study on the Regulation Mechanism of Ferroptosis in Diabetic Nephropathy Mice by Shenqi Dihuang Decoction through GPX4 Signaling Pathway
DOI:10.16466/j.issn1005-5509.2024.04.004
中文关键词: 参芪地黄汤  糖尿病肾病  铁死亡  脂质过氧化  GPX4信号通路  ROS  Steap3  GSH/GSSG
英文关键词: Shenqi Dihuang Decoction  diabetic nephropathy  ferroptosis  lipid peroxidation  GPX4 signaling pathway  ROS  Steap3  GSH/GSSG
基金项目:浙江省中医药科技计划项目(2023ZR134)
作者单位
王向晶 嘉兴市中医医院 浙江嘉兴 314000 
周奕菁 嘉兴市中医医院 浙江嘉兴 314000 
黄科 嘉兴市中医医院 浙江嘉兴 314000 
娄成利 嘉兴市中医医院 浙江嘉兴 314000 
徐秀琴 嘉兴市中医医院 浙江嘉兴 314000 
朱富祥 嘉兴市中医医院 浙江嘉兴 314000 
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中文摘要:
      [目的] 研究参芪地黄汤对糖尿病肾病(diabetic nephropathy,DN)模型小鼠的治疗效果及调控谷胱甘肽过氧化物酶4(glutathione peroxidase 4, GPX4)信号通路对铁死亡的影响。[方法] 通过链脲佐菌素(streptozotocin,STZ)联合高脂饮食诱导建立DN小鼠模型,并灌胃不同剂量的参芪地黄汤。通过检测各组小鼠体质量、血糖、肌酐(creatinine,Cr)、尿素氮(blood urea nitrogen,BUN)、24 h尿蛋白,肾石蜡切片苏木精-伊红(hematoxylin-eosin,HE)染色及过碘酸-雪夫(periodic acid-Schiff,PAS)染色评估参芪地黄汤对DN模型小鼠的治疗作用;通过检测丙二醛(malondialdehyde,MDA)、活性氧(reactive oxygen species,ROS)、4-羟基壬烯醛(4-hydroxynonenal,4-HNE)水平,评估参芪地黄汤对DN模型小鼠脂质过氧化水平的影响;通过检测总Fe水平以及转铁蛋白(transferin)、前列腺6跨膜上皮抗原3(six-transmembrane epithelial antigen of prostate 3,Steap3)蛋白水平评估参芪地黄汤对DN模型小鼠铁死亡的影响;通过检测还原型谷胱甘肽/氧化型谷胱甘肽(glutathione/oxidized glutathione,GSH/GSSG)水平以及溶质载体家族7成员11(solute carrier family 7 member 11,SLC7A11)、溶质载体家族3成员2(solute carrier family 3 member 2,SLC3A2)、GPX4、谷氨酸-半胱氨酸连接酶(glutamate cysteine ligase catalytic subunit,GCLC)、谷胱甘肽合成酶(glutathione synthetase,GSS)蛋白水平来评估参芪地黄汤对DN模型小鼠GPX4信号通路的影响。[结果] 与模型组比较,参芪地黄汤干预可明显提升DN模型小鼠体质量(P<0.01);降低DN小鼠血糖、Cr、BUN及24 h尿蛋白水平(P<0.05,P<0.01);同时改善DN模型小鼠肾组织病理学变化;降低MDA、ROS、4-HNE水平(P<0.01);降低总Fe水平(P<0.05,P<0.01)以及transferin、Steap3蛋白水平(P<0.05);升高GSH/GSSG比例(P<0.01)以及SLC7A11(P<0.05)、SLC3A2、GPX4、GCLC、GSS蛋白水平(P<0.05,P<0.01)。[结论] 参芪地黄汤对DN模型小鼠具有治疗作用,并且可以减轻脂质过氧化水平,其作用机制可能与通过调控GPX4信号通路抑制铁死亡有关。
英文摘要:
      [Objective] To investigate the therapeutic effect of Shenqi Dihuang Decoction(SQDH) on diabetic nephropathy(DN) model mice and its influence on ferroptosis through glutathione peroxidase 4(GPX4) signaling pathway. [Methods] The DN mouse model was established by streptozotocin(STZ) combined with high-fat diet, and different doses of SQDH decoction were administrated intragastrically. The body weight, blood glucose, creatinine(Cr), blood urea nitrogen(BUN),24 h urinary protein, paraffin section hematoxylin-eosin(HE) staining and periodic acid-Schiff(PAS) staining were used to evaluate the therapeutic effect of QSDH on DN model mice. The effects of SQDH on lipid peroxidation in DN mice were evaluated by measuring malondialdehyde(MDA), reactive oxygen species(ROS) and 4-hydroxynonenal(4-HNE) levels. By measuring the total level of Fe and transferin and six-transmembrane epithelial antigen of prostate 3(Steap3) to evaluate the effect of SQDH on ferroptosis. By measuring glutathione/oxidized glutathione(GSH/GSSG) level, as well as solute carrier family 7 member 11(SLC7A11), solute carrier family 3 member 2(SLC3A2), GPX4, glutamate cysteine ligase catalytic subunit(GCLC), glutathione synthetase(GSS) to evaluate the effect of SQDH on GPX4 signaling pathway in DN model mice. [Results] Compared with model group, SQDH could significantly increase the body weight of DN model mice(P<0.01). The levels of blood glucose, Cr, BUN and 24 h urinary protein in DN mice were decreased(P<0.05, P<0.01). At the same time, the renal histopathological changes of DN model mice were improved, the levels of MDA, ROS and 4-HNE were decreased(P<0.01). The total Fe level(P<0.05, P<0.01) and the protein levels of transferin and Steap3 were decreased(P<0.05). The ratio of GSH/GSSG(P<0.01) and protein levels of SLC7A11(P<0.05), SLC3A2, GPX4, GCLC and GSS(P<0.05, P<0.01) were increased. [Conclusion] SQDH has therapeutic effect on DN model mice, and can reduce the level of lipid peroxidation, the mechanism of which may be related to the inhibition of ferroptosis by regulating GPX4 signaling pathway.
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