Cell Death Pathways Drive Necroinflammation during Acute Kidney Injury

Abstract

Renal tubules represent an intercellular unit and function as a syncytium. When acute tubular necrosis was first visualized to occur through a process of synchronized regulated necrosis (SRN) in handpicked primary renal tubules, it became obvious that SRN actually promotes nephron loss. This realization adds to our current understanding of acute kidney injury (AKI)-chronic kidney disease (CKD) transition and argues for the prevention of AKI episodes to prevent CKD progression. Because SRN is triggered by necroptosis and executed by ferroptosis, 2 recently identified signaling pathways of regulated necrosis, a combination therapy employing necrostatins and ferrostatins may be beneficial for protection against nephron loss. Clinical trials in AKI and during the process of kidney transplantation are now required to prevent SRN. Additionally, necrotic cell death drives autoimmunity and necroinflammation and therefore represents a therapeutic target even for the prevention of antibody-mediated rejection of allografts years after the transplantation process.

Conditional knockout of TGF-βRII /Smad2 signals protects against acute renal injury by alleviating cell necroptosis, apoptosis and inflammation

“…We also identify hsa-miR-500a-3P directly target the 3'UTR of MLKL, thereby alleviates kidney injury via limiting necroptosis 41. Compared with apoptosis, necroptosis incurs more severe consequence because cells suffered necroptosis release endogenous pro-inflammatory molecules like damage-associated molecular patterns (DAMPs) and promote renal inflammation 42, 43. In the current study, our results showed that loss of Smad2 prevented, but overexpression of Smad2 promoted, cisplatin-activated necroptotic signaling, this result indicates Smad2 may play an important role in mediating cell necroptosis and consequent necroinflammation.…”

Ferroptosis: past, present and future

“…In addition, the relationship between ferroptosis and inflammation is also a hot research topic. Necrotic inflammation associated with ferroptosis has been observed in the kidneys in an AKI model induced by crystal (oxalate) and folic acid and in a GPX4 deletion mouse model 88 . Studies have found that GPX4 activation inhibits the activation of the arachidonic acid (AA) and nuclear factorkappa B (NF-κ B) pathways in the lipid peroxidationmediated inflammatory response, thereby reducing ROS levels in cells and inhibiting ferroptosis 89 .…”

“…The specific molecular mechanism is still unclear 4 . Increasing evidence shows that ferroptosis can be accompanied by inflammation, and that cells can activate innate immune system factors through ferroptosis stimulation and play a role in regulating inflammation damage, signal transduction, and cell growth 88,89 . Some studies have found that GPX4 activation can be used as a new anti-inflammatory or cytoprotective therapy 89 , but how can ferroptosis promote the development of inflammation?…”

The Role of PGC-1α and Mitochondrial Biogenesis in Kidney Diseases

“…The initial wave of tubular cell death is followed by tubular cell proliferation favoring regeneration, and by a second wave of cell death that adjusts the final cell number [5,6]. Regulated necrosis cell death through ferroptosis and necroptosis releases inflammatory cytokines that amplify tissue injury [7,8] while there is also evidence for a contribution of apoptotic cell death to kidney injury [9].…”