Mechanism of TGR5 in Ferroptosis of the Renal Tubular Epithelial Cells in Diabetes Mellitus and the Effect of Notoginsenoside Ft1

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.

Takeda G protein‐coupled receptor 5; diabetic kidney disease; ferroptosis; notoginsenoside Ft1; renal tubular epithelial cells.