Targeting ferroptosis as a prospective therapeutic approach for diabetic nephropathy

Abstract

Diabetic nephropathy (DN) is a severe complication of diabetes mellitus, causing a substantive threat to the public, which receives global concern. However, there are limited drugs targeting the treatment of DN. Owing to this, it is highly crucial to investigate the pathogenesis and potential therapeutic targets of DN. The process of ferroptosis is a type of regulated cell death (RCD) involving the presence of iron, distinct from autophagy, apoptosis, and pyroptosis. A primary mechanism of ferroptosis is associated with iron metabolism, lipid metabolism, and the accumulation of ROS. Recently, many studies testified to the significance of ferroptosis in kidney tissue under diabetic conditions and explored the drugs targeting ferroptosis in DN therapy. Our review summarized the most current studies between ferroptosis and DN, along with investigating the significant processes of ferroptosis in different kidney cells, providing a novel target treatment option for DN.

Keywords: Diabetic nephropathy; TEC; ferroptosis; glomerular endothelial cell; mesangial cell; podocyte.

Figure 1.

In diabetic nephropathy, high glucose stimulates ferroptosis in kidney cells including tubular epithelial cells, podocytes, glomerular endothelial cells, and mesangial cells.

Figure 2.

Overview of the ferroptosis mechanism. Primary regulatory pathways of ferroptosis might be summarized as the influence of lipid metabolism, ROS accumulation, and iron metabolism. GSH, glutathione; GPX4, glutathione peroxidase 4; LIP, labile iron pool; Nrf2, nuclear-factor- erythroid2-related factor 2; TRF, transferrin; LPO, lipid peroxide; H2O2, hydrogen peroxide; · OH, producing toxic hydroxyl radicals; Fe2+, divalent iron ionization; PUFAs, polyunsaturated fatty acids; ROS, reactive oxygen species; Cys, cystine; Glu, glutamate; PRMT4, Protein Arginine Methyltransferase 4; KLF2, Kruppel-like factor 2; This figure is created with BioRender.com.