Advanced oxidation protein products induce apoptosis in podocytes through induction of endoplasmic reticulum stress

Abstract

Although podocyte apoptosis has been shown to be induced by the accumulation of advanced oxidation protein products (AOPPs), the mechanisms through which AOPPs trigger apoptosis in these cells remain unclear. In this study, we investigated the role of endoplasmic reticulum (ER) stress in AOPP-induced podocyte apoptosis. AOPP treatment induced overexpression of glucose-regulated protein 78 and CCAAT/enhancer-binding protein-homologous protein (CHOP) in podocytes, indicating that AOPPs induced ER stress. Notably, AOPP-induced increase in the rate of podocyte apoptosis was partly reversed by salubrinal, an ER stress inhibitor, whereas the AOPP effect was reproduced by an inducer of ER stress, thapsigargin, suggesting that AOPPs triggered podocyte apoptosis by inducing ER stress. Furthermore, AOPP-induced reactive oxygen species (ROS) generation, ER stress, and podocyte apoptosis were significantly inhibited by an nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, a ROS scavenger, or receptor of advanced glycation end products (RAGE) small interfering RNA (siRNA). Moreover, silencing of the three ER stress sensors, protein kinase-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol requiring 1 (IRE1), respectively, significantly lowered the apoptotic rate of the cells compared with that of the scramble siRNA-transfected cells. Lastly, our data suggested that CHOP- and caspase-12-dependent pathways were involved in ER stress-mediated podocyte apoptosis and that Bcl-2 suppression was involved in CHOP-mediated apoptosis. Collectively, our results indicate for the first time that AOPPs trigger podocyte apoptosis through induction of ER stress, which might be regulated by NADPH oxidase-dependent ROS through RAGE, and that this apoptosis is mediated by three unfolded protein response pathways, the PERK, ATF6, and IRE1 pathways, and the mediators, CHOP and caspase-12.

APOL1 risk variants cause podocytes injury through enhancing endoplasmic reticulum stress

“…Increasing evidence suggest that ER stress contribute to glomerular and tubular cell injury in kidney diseases [ 19–21 ]. In response to ER stress, three UPR signal transduction pathways are initiated by three transmembrane proteins: protein kinase-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol requiring 1 (IRE1) [ 22 ]. The subsequence of activation of PERK is to cause the phosphorylation of eukaryotic translation initiation factor (eIF)-2α, which further causes the down-regulation of translation.…”

“…The accumulation of misfolded/unfolded proteins in the ER and alterations in calcium homeostasis lead to ER stress, which leads to the unfolded protein response (UPR, a series of integrative stress pathways). ER stress has been widely demonstrated to contribute to both glomerular and tubular cell injuries in kidney diseases [ 19–21 ]; moreover, it has been shown to be a mediator of podocyte apoptosis [ 22–25 ].…”

Advanced glycation end products inhibit testosterone secretion by rat Leydig cells by inducing oxidative stress and endoplasmic reticulum stress

“…Furthermore, recent studies have indicated that AGEs can also adversely affect endoplasmic reticulum function, leading to pathogenic endoplasmic reticulum stress (38)(39)(40)(41). Inhibitors of advanced glycation acting as potent endoplasmic reticulum stress modulators with beneficial effects in restoring endoplasmic reticulum homeostasis and adjusting the physiological unfolded protein response level, present an emerging therapeutic approach with significant applications, particularly in the context of metabolic dysfunction (42).…”

Research Progress on Mechanism of Podocyte Depletion in Diabetic Nephropathy

“…It could induce glomerular obstacle of podocyte structure and function, participate in a variety of kidney diseases, and also lead to glomerular sclerosis [ 66 ]. Continuous endoplasmic reticulum stress had effects on the function of endoplasmic reticulum and could launch apoptosis signaling pathways which were mediated by endoplasmic reticulum stress at the same time and then activated the downstream apoptotic signaling molecules [ 67 ]. In patients with diabetes, hyperglycemia can motivate endoplasmic reticulum stress through a variety of ways, then cause cellular damage [ 68 ].…”