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Review
. 2024 Feb 12:15:1308733.
doi: 10.3389/fphar.2024.1308733. eCollection 2024.

Acute kidney injury: exploring endoplasmic reticulum stress-mediated cell death

Cong Cheng  1 , Yuan Yuan  2 , Fang Yuan  3   4 , Xin Li  3   4
Affiliations
Review

Acute kidney injury: exploring endoplasmic reticulum stress-mediated cell death

Cong Cheng et al. Front Pharmacol. .

Abstract

Acute kidney injury (AKI) is a global health problem, given its substantial morbidity and mortality rates. A better understanding of the mechanisms and factors contributing to AKI has the potential to guide interventions aimed at mitigating the risk of AKI and its subsequent unfavorable outcomes. Endoplasmic reticulum stress (ERS) is an intrinsic protective mechanism against external stressors. ERS occurs when the endoplasmic reticulum (ER) cannot deal with accumulated misfolded proteins completely. Excess ERS can eventually cause pathological reactions, triggering various programmed cell death (autophagy, ferroptosis, apoptosis, pyroptosis). This article provides an overview of the latest research progress in deciphering the interaction between ERS and different programmed cell death. Additionally, the report consolidates insights into the roles of ERS in AKI and highlights the potential avenues for targeting ERS as a treatment direction toward for AKI.

Keywords: acute kidney injury; apoptosis; autophagy; endoplasmic reticulum stress; ferroptosis; pyroptosis.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Schematic of the three signaling pathways during UPR induced by ERS (IRE1α, ATF6, and PERK). ER transmembrane proteins mainly include IRE1, PERK and ATF6. Following ERS, unfolded proteins are accumulated in the ER lumen. The three branches from three ER transmembrane stress sensors are activated that shape the UPR. PERK dimerizes, gets phosphorylated, and activated causing phosphorylation of eIF2α. Activated eIF2α suppress global protein synthesis inhibition but stimulates the translation of ATF4. IRE1α oligomerizes and auto-phosphorylates and its RNase domain becomes active and targets XBP1 mRNA, leading to the expression of the spliced form of XBP1 (XBP1s). Activated ATF6 translocate to the Golgi and is sequentially cleaved by the Golgi-resident site-1 and site-2 proteases (S1P and S2P), thereby releasing cleaved ATF6. The transcription factors ATF4, XBP1 and ATF6 enter the nucleus and regulates downstream UPR gene, resulting in cell survival or death.
FIGURE 2
FIGURE 2
The link between ERS and apoptosis. Under overwhelming conditions of ERS, the UPR induces the activation of both intrinsic and extrinsic apoptosis pathways. Death receptor-mediated extrinsic apoptosis Receptor-mediated pathways are initiated by death-ligands that bind to their specific death receptors, which include TNF, Fas and TNF-related apoptosis-inducing ligand (TRAIL) receptor (DR4, DR5). The intrinsic pathway of apoptosis is comprised with mitochondria pathway and ERS pathway. Mitochondrial apoptosis pathway is induced by BCL-2 family proteins (including anti-apoptosis proteins and pro-apoptosis proteins), while ERS apoptosis pathway is induced by caspase-8. After a series of reactions, intrinsic and extrinsic apoptosis pathways eventually trigger cell apoptosis.
FIGURE 3
FIGURE 3
The link between ERS and autophagy. ERS could activate autophagy, the UPR can regulate expression of autophagy gene (Atg3, Atg5, Atg7, Atg10, LC3B, P62) and autophagosome formation. Autophagy begins with autophagosome formation, LC3B localizes on the surface of autophagic vesicle membrane and participates in autophagosome formation. With autophagy proceeds, autophagosome fuse with lysosomes generates an autophagolysosome and results in degradation.
FIGURE 4
FIGURE 4
The link between ERS and ferroptosis. Under ERS, the three branches of UPR can regulate ferroptosis through iron metabolism system, GPX4 antioxidant system, and lipid peroxidation system. The accumulation of Fe2+ and PUFA-OOH or the inactivation of GPX4 antioxidant system all induce the production of lipid peroxides (LPO), resulted in ferroptosis.
FIGURE 5
FIGURE 5
The link between ERS and pyroptosis. Pyroptosis can be categorized in two distinct ways: caspase-1-dependent classical inflammasome signaling and caspase-4/5/11-dependent nonclassical inflammasome signaling. Activated caspase-1 and caspases-4/5/11 cleave GSDMD into a N-terminal fragment of GSDMD (GSDMD-N) and promote maturation of IL-1β and IL-18. GSDMD-N can bind and form pores at cell membrane, leading to the release pro-inflammatory cytokines (IL-1β, IL-18) and the progress of inflammation and pyroptosis.
FIGURE 6
FIGURE 6
The dichotomous effect of ERS in AKI. ERS and the activation of the UPR pathway occur during IRI, nephrotoxic agents or sepsis induction. Depending on the intensity of the ERS, UPR activation can directly affect the occurrence and progress of apoptosis, autophagy, ferroptosis and pyoptosis, then lead to cell survival or death, finally determine the development of AKI.
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Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The manuscript was supported by the Hunan Provincial Key Laboratory of Anti-Resistance Microbial Drugs (No: 2023TP1013), the Changsha Science and Technology Project (No: kq2208464), the Project of Changsha Municipal Health Commission (No: KJ-B2023064).

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