caa a22 4500 606235655 CHVBK 20210128101243.0 cr unu---uuuuu 210128e20150901xx s 000 0 eng 10.1007/s11010-015-2469-0 doi (NATIONALLICENCE)springer-10.1007/s11010-015-2469-0 ATF6 pathway of unfolded protein response mediates advanced oxidation protein product-induced hypertrophy and epithelial-to-mesenchymal transition in HK-2 cells [Elektronische Daten] [Xun Tang, Xiujie Liang, Minhui Li, Tingting Guo, Na Duan, Yue Wang, Guang Rong, Lei Yang, Shaojie Zhang, Jun Zhang] Advanced oxidation protein products (AOPPs) accelerate the progression of chronic kidney disease. We previously demonstrated that AOPPs induce hypertrophy and epithelial-to-mesenchymal transition (EMT) in human proximal tubular cells (HK-2 cells) through induction of endoplasmic reticulum (ER) stress. However, which pathway of unfolded protein response (UPR) induced by ER stress plays crucial roles in this process remains unclear. In this study, we investigated the roles of the protein kinase RNA-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1 (IRE1) pathways of UPR in this process in HK-2 cells. AOPP treatment induced the overexpression of cleaved ATF6 and spliced form of X-box binding protein-1, and induced the phosphorylation of PERK, eukaryotic translation initiation factor 2α and IRE1. Furthermore, silencing of ATF6 increased E-cadherin and zonula occludens-1 expression, lowered the expression of vimentin, and downregulated total protein content, whereas knockdown of PERK or IRE1 resulted in no difference compared with the scramble siRNA-transfected cells. AOPP-induced phosphorylation of Src, which was reproduced by thapsigargin, an inducer of ER stress, was partly reversed by salubrinal, an inhibitor of ER stress. Furthermore, the Src inhibitor saracatinib effectively blocked AOPP-induced phosphorylation of Src, activation of ER stress, hypertrophy, and EMT in HK-2 cells. Collectively, our results indicate that AOPPs induce the PERK, ATF6, and IRE1 pathways of UPR, and the ATF6 pathway rather than the other two pathways mediates AOPP-induced HK-2-cell hypertrophy and EMT. We also suggest that the ER stress involved in this process is likely mediated by the activation of Src kinase. Springer Science+Business Media New York, 2015 Unfolded protein response (UPR) nationallicence Advanced oxidation protein products (AOPPs) nationallicence Epithelial-to-mesenchymal transition (EMT) nationallicence Hypertrophy nationallicence Endoplasmic reticulum stress nationallicence Tang Xun Department of Nephrology, Zhujiang Hospital, Southern Medical University, No. 253, Gongye Road, Haizhu District, 510280, Guangzhou, Guangdong, China aut Liang Xiujie Department of Nephrology, Zhujiang Hospital, Southern Medical University, No. 253, Gongye Road, Haizhu District, 510280, Guangzhou, Guangdong, China aut Li Minhui Southern Medical University, Guangzhou, Guangdong, China aut Guo Tingting Department of Nephrology, Zhujiang Hospital, Southern Medical University, No. 253, Gongye Road, Haizhu District, 510280, Guangzhou, Guangdong, China aut Duan Na Department of Nephrology, Zhujiang Hospital, Southern Medical University, No. 253, Gongye Road, Haizhu District, 510280, Guangzhou, Guangdong, China aut Wang Yue Department of Nephrology, Zhujiang Hospital, Southern Medical University, No. 253, Gongye Road, Haizhu District, 510280, Guangzhou, Guangdong, China aut Rong Guang Department of Nephrology, Shilong People's Hosiptal, Southern Medical University, Dongguan, Guangdong, China aut Yang Lei Department of Nephrology, Zhujiang Hospital, Southern Medical University, No. 253, Gongye Road, Haizhu District, 510280, Guangzhou, Guangdong, China aut Zhang Shaojie College of Arts and Science, Syracuse University, Syracuse, USA aut Zhang Jun Department of Nephrology, Zhujiang Hospital, Southern Medical University, No. 253, Gongye Road, Haizhu District, 510280, Guangzhou, Guangdong, China aut Molecular and Cellular Biochemistry Springer US; http://www.springer-ny.com 407/1-2(2015-09-01), 197-207 0300-8177 407:1-2<197 2015 407 11010 https://doi.org/10.1007/s11010-015-2469-0 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s11010-015-2469-0 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Tang Xun Department of Nephrology, Zhujiang Hospital, Southern Medical University, No. 253, Gongye Road, Haizhu District, 510280, Guangzhou, Guangdong, China aut NATIONALLICENCE 700 1- Liang Xiujie Department of Nephrology, Zhujiang Hospital, Southern Medical University, No. 253, Gongye Road, Haizhu District, 510280, Guangzhou, Guangdong, China aut NATIONALLICENCE 700 1- Li Minhui Southern Medical University, Guangzhou, Guangdong, China aut NATIONALLICENCE 700 1- Guo Tingting Department of Nephrology, Zhujiang Hospital, Southern Medical University, No. 253, Gongye Road, Haizhu District, 510280, Guangzhou, Guangdong, China aut NATIONALLICENCE 700 1- Duan Na Department of Nephrology, Zhujiang Hospital, Southern Medical University, No. 253, Gongye Road, Haizhu District, 510280, Guangzhou, Guangdong, China aut NATIONALLICENCE 700 1- Wang Yue Department of Nephrology, Zhujiang Hospital, Southern Medical University, No. 253, Gongye Road, Haizhu District, 510280, Guangzhou, Guangdong, China aut NATIONALLICENCE 700 1- Rong Guang Department of Nephrology, Shilong People's Hosiptal, Southern Medical University, Dongguan, Guangdong, China aut NATIONALLICENCE 700 1- Yang Lei Department of Nephrology, Zhujiang Hospital, Southern Medical University, No. 253, Gongye Road, Haizhu District, 510280, Guangzhou, Guangdong, China aut NATIONALLICENCE 700 1- Zhang Shaojie College of Arts and Science, Syracuse University, Syracuse, USA aut NATIONALLICENCE 700 1- Zhang Jun Department of Nephrology, Zhujiang Hospital, Southern Medical University, No. 253, Gongye Road, Haizhu District, 510280, Guangzhou, Guangdong, China aut NATIONALLICENCE 773 0- Molecular and Cellular Biochemistry Springer US; http://www.springer-ny.com 407/1-2(2015-09-01), 197-207 0300-8177 407:1-2<197 2015 407 11010