The emerging role of regulated cell death in ischemia and reperfusion-induced acute kidney injury: current evidence and future perspectives

Abstract

Renal ischemia‒reperfusion injury (IRI) is one of the main causes of acute kidney injury (AKI), which is a potentially life-threatening condition with a high mortality rate. IRI is a complex process involving multiple underlying mechanisms and pathways of cell injury and dysfunction. Additionally, various types of cell death have been linked to IRI, including necroptosis, apoptosis, pyroptosis, and ferroptosis. These processes operate differently and to varying degrees in different patients, but each plays a role in the various pathological conditions of AKI. Advances in understanding the underlying pathophysiology will lead to the development of new therapeutic approaches that hold promise for improving outcomes for patients with AKI. This review provides an overview of the recent research on the molecular mechanisms and pathways underlying IRI-AKI, with a focus on regulated cell death (RCD) forms such as necroptosis, pyroptosis, and ferroptosis. Overall, targeting RCD shows promise as a potential approach to treating IRI-AKI.

Fig. 1. Human kidney biopsy with IRI-AKI (cortical area).

Ischemia is a condition in which the kidneys do not receive enough blood supply. Reperfusion is the restoration of blood flow after an ischemic event. Both of these processes can damage kidney cells and impair kidney function, resulting in AKI. This can cause expansion of the interstitium, microvascular plugging, dilated tubules, and a patchy nature of injury, ultimately leading to various types of RCD. Several risk factors can contribute to the development of IRI-AKI. AKI acute kidney injury, IRI ischemia-reperfusion injury, RCD regulated cell death, TEC tubular epithelial cell, DC dendritic cells, RBC red blood cell, WBC white blood cell, DAMPs damage-associated molecular patterns.

Fig. 2. The interplay of molecular mechanisms in apoptosis, necroptosis, and pyroptosis.

Both necroptosis and pyroptosis interact with apoptosis through the caspase family of proteins. a In the extrinsic apoptosis pathway, death receptors TNFR activate caspase-8, which in turn activates caspases and may also progress BID to tBID, activating the mitochondrial apoptotic pathway. Inhibitor of apoptosis (IAP) proteins activate NF-κB to increase the transcription of antiapoptotic proteins. b Necroptosis is programmed and regulated by RIPK1 and RIPK3, which form a necrosome in the presence of various stimuli and inhibition of caspase-8 and cIAPs. Phosphorylated MLKL induced by the necrosome oligomerizes to form pores that disrupt the plasma membrane, allowing the release of cell contents. c In the intrinsic apoptosis pathway, the imbalance between BCL-2 proteins and BH3-only proteins leads to mitochondrial outer membrane permeabilization. This causes the release of proapoptotic mitochondrial proteins, including cytochrome c, and the formation of the apoptosome (APAF1 and procaspase-9). Activation of caspase-9 then triggers the activation of executioner caspases (such as caspase-3 and caspase-7) that dismantle cell structures. d Pyroptosis is a process in which gasdermins are enzymatically processed into amino-terminal (NT) fragments. These fragments then assemble to form pores in the cell membrane. Danger signals, such as DAMPs, activate the inflammasome, which in turn triggers caspase-1 activation. Caspase-1 is involved in the maturation of IL-18 and IL-1β, and it also cleaves GSDMD to generate N-terminal fragments that create pores in the cell membrane. GSDMD can also be cleaved by caspases-4, 5, and 11 through a noncanonical pathway. Furthermore, gasdermins can cause mitochondrial permeabilization. There are also connections between pyroptosis and apoptosis, with caspase-3 cleaving gasdermin E (GSDME) and caspase-8 cleaving GSDMD.

Fig. 3. Main mechanisms of ferroptosis.

Ferroptosis is a process characterized by the accumulation of lipid ROS. To prevent this accumulation, sufficient levels of GSH are maintained through the uptake of cystine via the system xc−cystine/glutamate antiporter. The antioxidant function of GPX4 depends on GSH. Another antioxidant system involves FSP1, which helps maintain vitamin K and CoQ10 in a reduced state. The main outcome of ferroptosis is the peroxidation of membrane phospholipids, resulting in membrane rupture. ROS reactive oxygen species, GPX4 glutathione peroxidase 4, GSH glutathione, CoQ10 coenzyme Q10.