Oxalate-induced apoptosis through ERS-ROS–NF-κB signalling pathway in renal tubular epithelial cell

Abstract

Background Kidney stones are composed of approximately 70–80% calcium oxalate. However, the exact mechanism of formation of calcium oxalate kidney stones remains unclear. In this study, we investigated the roles of endoplasmic reticulum stress (ERS), reactive oxygen species (ROS), and the NF-κB signalling pathway in the pathogenesis of oxalate-induced renal tubular epithelial cell injury and its possible molecular mechanisms. Methods We established a model to evaluate the formation of kidney stones by intraperitoneal injection of glyoxylic acid solution into mice and assessed cell morphology, apoptosis, and the expression levels of ERS, ROS, and NF-κB signalling pathway-related proteins in mouse renal tissues. Next, we treated HK-2 cells with potassium oxalate to construct a renal tubular epithelial cell injury model. We detected the changes in autophagy, apoptosis, and mitochondrial membrane potential and investigated the ultrastructure of the cells by transmission electron microscopy. Western blotting revealed the expression levels of apoptosis and autophagy proteins; mitochondrial structural and functional proteins; and ERS, ROS, and NF-κB (p65) proteins. Lastly, we studied the downregulation of NF-κB activity in HK-2 cells by lentivirus interference and confirmed the interaction between the NF-κB signalling and ERS/ROS pathways. Results We observed swelling of renal tissues, increased apoptosis of renal tubular epithelial cells, and activation of the ERS, ROS, and NF-κB signalling pathways in the oxalate group. We found that oxalate induced autophagy, apoptosis, and mitochondrial damage in HK-2 cells and activated the ERS/ROS/NF-κB pathways. Interestingly, when the NF-κB signalling pathway was inhibited, the ERS/ROS pathway was also inhibited. Conclusion Oxalate induces HK-2 cell injury through the interaction between the NF-κB signalling and ERS/ROS pathways.

CDCT‐induced nephrotoxicity in rat by apoptosis via metabolic disturbance

“…The results indicating that apoptosis is close with the disruption of CL. Moreover, an increasing amount of research has demonstrated that LTB 4 can serve as a trigger for apoptosis (Mangolini et al, 2010; Ming et al, 2022). It implies that there are likely multiple mechanisms involved in the activation of caspase in response to CDCT exposure.…”

Epithelial–mesenchymal plasticity in kidney fibrosis

“…In addition to the stimuli described above, reactive oxygen species (ROS) is a potent inducer mediating EMT particularly in peritubular microenvironment (Figure 3). The increased level of intracellular ROS can cause oxidation of lipids, DNAs, and proteins, leading to cell damage/injury (Ming et al, 2022; Wu et al, 2023). ROS also acts as a secondary messenger in cellular signaling pathways (Ming et al, 2022; Wu et al, 2023).…”

“…The increased level of intracellular ROS can cause oxidation of lipids, DNAs, and proteins, leading to cell damage/injury (Ming et al, 2022; Wu et al, 2023). ROS also acts as a secondary messenger in cellular signaling pathways (Ming et al, 2022; Wu et al, 2023). When ROS increases in TECs, the cells release proinflammatory cytokines and chemokines for repairing mechanism.…”

“…When ROS increases in TECs, the cells release proinflammatory cytokines and chemokines for repairing mechanism. Nevertheless, uncontrolled or prolonged ROS production results in inflammation and fibrosis (Ming et al, 2022; Wu et al, 2023). All the stimuli mentioned above and several other factors can induce intracellular ROS overproduction in kidney tissue.…”

Heat Stress-Induced Intestinal Barrier Impairment: Current Insights into the Aspects of Oxidative Stress and Endoplasmic Reticulum Stress

“…Further, it has been demonstrated that HS increases NF-κB and interleukin-1β (IL-1β) expression and participates in the inflammatory response. , Overactivation of the UPR cascades is considered to be a major cause of inflammatory response in the gut. The three UPR signalings of ERS can activate the NF-κB pathway; for example, IRE1α/TRAF2 can evoke NF-κB via Nucleotide Binding Oligomerization Domain Containing 1/2 (NOD1/NOD2), while phosphorylated eIF2α activates the NF-κB pathway by inhibiting the synthesis of inhibitor of κB (IκB) . Recent research has also revealed an involvement of ROS in NF-κB signaling initiation via IκB phosphorylation .…”