Advanced oxidation protein products induce apoptosis in podocytes through induction of endoplasmic reticulum stress
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ORIGINAL PAPER
Advanced oxidation protein products induce apoptosis in podocytes through induction of endoplasmic reticulum stress Guang Rong & Xun Tang & Tingting Guo & Na Duan & Yue Wang & Lei Yang & Jun Zhang & Xiujie Liang
Received: 26 January 2015 / Accepted: 6 July 2015 # University of Navarra 2015
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 Guang Rong and Xun Tang contributed equally to this work. G. Rong : X. Tang : T. Guo : N. Duan : Y. Wang : L. Yang : J. Zhang (*) : X. Liang (*) Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, People’s Republic of China e-mail: [email protected] e-mail: [email protected]
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 CHOPmediated 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. Keywords Advanced oxidation protein products (AOPPs) . Podocyte . Apoptosis . Endoplasmic reticulum stress . Unfolded protein response
Introduction Diabetic nephropathy (DN) is a leading cause of endstage renal disease worldwide, and it is a serious public health concern. A prominent clinical feature of DN and an independent risk factor for DN progression is proteinuria, which is a consequence of the disruption of the glomerular filtration barrier [15]. In the maintenance of glomerular permeabi
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