Unveiling CHOP's Role in Ischemic Acute Kidney Injury

Abstract

In clinical settings, renal ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury (AKI), which often progresses to acute renal failure or end-stage renal disease (ERAD). The current understanding of the molecular mechanisms underlying IRI induced tubular cell injury remain unclear. Therefore, identifying effective strategies to reduce renal IRI remains a scientific challenge. In this study, we investigated the unfolded protein response (UPR), specifically the contribution of the pro-apoptotic transcription factor C/EBP homologous protein (CHOP) in regulating endoplasmic reticulum (ER) stress induced injury under ischemia and IRI mimicking conditions. Our research reveals that low glucose, no glucose and hypoxia, components of ischemia, increases CHOP expression and tubular cell death. Furthermore, when the components of ischemia were combined with reoxygenation, to model renal IRI conditions, CHOP expression and cell death were also increased. Interestingly, our study also identified that CHOP upregulation is not only associated with increased CHOP expression and tubular cell death, but also with the cleavage of Gasdermin E (GSDME), a protein that plays an important role in mediating pyroptosis, a type of inflammation regulated programmed cell death. To further elucidate the role of UPR signaling in mediating CHOP induced injury, we investigated pharmacological inhibitors targeting specific UPR branches. Inhibition of the Protein kinase R-like endoplasmic reticulum kinase (PERK) pathway with GSK2606414 reduced CHOP expression and protected against tubular cell death, while IRE1α inhibition with 4μ8c decreased tubular cell death without affecting CHOP expression. However, inhibition of ATF6 using Ceapin-A7 had negligible effects on CHOP expression and tubular cell death. Therefore, this study highlights CHOP as a key mediator of IRI induced injury and pyroptosis in renal cells, and suggests that the targeted inhibition of the PERK-CHOP axis may offer a novel therapeutic strategy for ischemic AKI.