{"title":"Mechanism of TGR5 in Ferroptosis of the Renal Tubular Epithelial Cells in Diabetes Mellitus and the Effect of Notoginsenoside Ft1","authors":"Xiang Xiao, Junlin Zhang, Yucheng Wu, Qing Yang, Yutong Zhou, Jia Yang, Yanlin Lang, Linli Cai, Xuegui Ju, Fang Liu","doi":"10.1096/fj.202402534R","DOIUrl":null,"url":null,"abstract":"<div>\n \n <p>TGR5 and its agonists have the role of regulating glycolipid metabolism. The ferroptosis of renal tubular epithelial cells (TECs) caused by glycolipid metabolism disorders participates in the process of DKD. This study aims to explore the relationship between TGR5 activation and the intervention of notoginsenoside Ft1 (Ft1) and the ferroptosis of diabetic renal TECs, as well as the possible molecular mechanism. By using adeno-associated virus 9 (AAV9) to overexpress TGR5 or Ft1 to intervene in db/db mice, the effects on renal injury and ferroptosis are observed. In addition, by inducing HK2 cells with high glucose and palmitic acid (HGPA) to simulate the injury model of diabetic TECs, the effects and molecular mechanisms of plasmid transfection for overexpressing TGR5, siRNA silencing TGR5 expression, and Ft1 intervention on ferroptosis are respectively observed. In db/db mice, overexpression of TGR5 or Ft1 intervention alleviated kidney damage, manifested as a reduction in proteinuria, mesangial matrix expansion, and an alleviation of tubular injury. In HK2 cultured with HGPA, overexpression of TGR5 or Ft1 intervention could both inhibit ferroptosis of TECs, while silencing the expression of TGR5 further promoted ferroptosis of TECs. The JNK signaling pathway played an important role in this process. These findings confirm the significant role of TGR5 activation or Ft1 intervention in diabetic TECs injury and ferroptosis, and imply that TGR5 may be a potential therapeutic target for diabetic TECs injury and ferroptosis, while Ft1 may be a potent drug for the treatment of DKD.</p>\n </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 12","pages":""},"PeriodicalIF":4.2000,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"The FASEB Journal","FirstCategoryId":"99","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1096/fj.202402534R","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
TGR5 and its agonists have the role of regulating glycolipid metabolism. The ferroptosis of renal tubular epithelial cells (TECs) caused by glycolipid metabolism disorders participates in the process of DKD. This study aims to explore the relationship between TGR5 activation and the intervention of notoginsenoside Ft1 (Ft1) and the ferroptosis of diabetic renal TECs, as well as the possible molecular mechanism. By using adeno-associated virus 9 (AAV9) to overexpress TGR5 or Ft1 to intervene in db/db mice, the effects on renal injury and ferroptosis are observed. In addition, by inducing HK2 cells with high glucose and palmitic acid (HGPA) to simulate the injury model of diabetic TECs, the effects and molecular mechanisms of plasmid transfection for overexpressing TGR5, siRNA silencing TGR5 expression, and Ft1 intervention on ferroptosis are respectively observed. In db/db mice, overexpression of TGR5 or Ft1 intervention alleviated kidney damage, manifested as a reduction in proteinuria, mesangial matrix expansion, and an alleviation of tubular injury. In HK2 cultured with HGPA, overexpression of TGR5 or Ft1 intervention could both inhibit ferroptosis of TECs, while silencing the expression of TGR5 further promoted ferroptosis of TECs. The JNK signaling pathway played an important role in this process. These findings confirm the significant role of TGR5 activation or Ft1 intervention in diabetic TECs injury and ferroptosis, and imply that TGR5 may be a potential therapeutic target for diabetic TECs injury and ferroptosis, while Ft1 may be a potent drug for the treatment of DKD.
期刊介绍:
The FASEB Journal publishes international, transdisciplinary research covering all fields of biology at every level of organization: atomic, molecular, cell, tissue, organ, organismic and population. While the journal strives to include research that cuts across the biological sciences, it also considers submissions that lie within one field, but may have implications for other fields as well. The journal seeks to publish basic and translational research, but also welcomes reports of pre-clinical and early clinical research. In addition to research, review, and hypothesis submissions, The FASEB Journal also seeks perspectives, commentaries, book reviews, and similar content related to the life sciences in its Up Front section.