Modes of podocyte death in diabetic kidney disease: an update

Diabetic kidney disease (DKD) accounts for a large proportion of end-stage renal diseases that require renal replacement therapies including dialysis and transplantation. Therefore, it is critical to understand the occurrence and development of DKD. Podocytes are mainly injured during the development of DKD, ultimately leading to their extensive death and loss. In turn, the injury and death of glomerular podocytes are also the main culprits of DKD. This review introduces the characteristics of podocytes and summarizes the modes of their death in DKD, including apoptosis, autophagy, mitotic catastrophe (MC), anoikis, necroptosis, and pyroptosis. Apoptosis is characterized by nuclear condensation and the formation of apoptotic bodies, and it exerts a different effect from autophagy in mediating DKD-induced podocyte loss. MC mediates a faulty mitotic process while anoikis separates podocytes from the basement membrane. Moreover, pyroptosis activates inflammatory factors to aggravate podocyte injuries whilst necroptosis drives signaling cascades, such as receptor-interacting protein kinases 1 and 3 and mixed lineage kinase domain-like, ultimately promoting the death of podocytes. In conclusion, a thorough knowledge of the modes of podocyte death in DKD can help us understand the development of DKD and lay the foundation for strategies in DKD disease therapy.Graphical abstract