Oncotarget

Research Papers:

Ochratoxin A induces ER stress and apoptosis in mesangial cells via a NADPH oxidase-derived reactive oxygen species-mediated calpain activation pathway

Meei-Ling Sheu, Chin-Chang Shen, Yuan-Siao Chen and Chih-Kang Chiang _

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Oncotarget. 2017; 8:19376-19388. https://doi.org/10.18632/oncotarget.14270

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Abstract

Meei-Ling Sheu1,2,3,*, Chin-Chang Shen4,*, Yuan-Siao Chen5, Chih-Kang Chiang5,6

1Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan

2Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan

3Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan

4Chemical Engineering Division, Institute of Nuclear Energy Research, Atomic Energy Council, Longtan District, Taoyuan, Taiwan

5Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan

6Department of Integrated Diagnostics & Therapeutics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan

*These authors have contributed equally in this work

Correspondence to:

Chih-Kang Chiang, email: [email protected]

Keywords: ochratoxin A, mesangial cells, NADPH oxidase, ER stress, apoptosis

Received: September 02, 2016     Accepted: November 30, 2016     Published: December 27, 2016

ABSTRACT

Ochratoxin A (OTA) contaminated food increases reactive oxygen species (ROS) production in glomerulus and causes glomerulopathy. The molecular mechanisms still remain uncertain. In this study, we used mouse and rat glomerular mesangial cells and delineate the signaling pathway behind the OTA-triggered cell apoptosis. OTA dose-dependently induced expression of ER stress markers including phospho-PERK, phospho-eIF2α, GRP78, GRP94, and CHOP. Apoptosis events including cleavage of caspase-12, caspase-7, and PARP are also observed. OTA activated oxidative stress and increased NADPH oxidase activity. NADPH oxidase inhibitor, apocynin, significantly attenuated OTA-induced cell apoptosis. Moreover, OTA markedly increased the calpain activity which significantly inhibited by apocynin. Transfection of calpain-siRNA effectively inhibited the OTA-increased ER stress-related protein expression. These findings suggest that OTA activated NADPH oxidase and calpain, induced ER stress and ROS production, and caused glomerular mesangial cells apoptosis which leads to glomerulopathy.


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