Bo Lin Chen1, Meei Ling Sheu2, Keh Sung Tsai3, Kuo Cheng Lan4, Siao Syun Guan1, Cheng Tien Wu1, Li Ping Chen5, Kuan Yu Hung6, Jenq Wen Huang6, Chih Kang Chiang1,7, Shing Hwa Liu1,8,9. 1. 1 Institute of Toxicology, College of Medicine, National Taiwan University , Taipei, Taiwan . 2. 2 Institute of Biomedical Sciences, National Chung Hsing University , Taichung, Taiwan . 3. 3 Department of Laboratory Medicine, College of Medicine, National Taiwan University , Taipei, Taiwan . 4. 4 Department of Emergency Medicine, National Defense Medical Center, Tri-Service General Hospital , Taipei, Taiwan . 5. 5 Department of Dentistry, Taipei Chang Gang Memorial Hospital, Chang Gang University , Taipei, Taiwan . 6. 6 Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine , Taipei, Taiwan . 7. 7 Department of Integrated Diagnostics and Therapeutics, College of Medicine and Hospital, National Taiwan University , Taipei, Taiwan . 8. 8 Department of Medical Research, China Medical University Hospital, China Medical University , Taichung, Taiwan . 9. 9 Department of Pediatrics, National Taiwan University Hospital , Taipei, Taiwan .
Abstract
AIMS: Renal ischemia-reperfusion (I/R) is a major cause of acute renal failure. The mechanisms of I/R injury include endoplasmic reticulum (ER) stress, inflammatory responses, hypoxia, and generation of reactive oxygen species (ROS). CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) is involved in the ER stress signaling pathways. CHOP is a transcription factor and a major mediator of ER stress-induced apoptosis. However, the role of CHOP in renal I/R injury is still undefined. Here, we investigated whether CHOP could regulate I/R-induced renal injury using CHOP-knockout mice and cultured renal tubular cells as models. RESULTS: In CHOP-knockout mice, loss of renal function induced by I/R was prevented. Renal proximal tubule damage was induced by I/R in wild-type mice; however, the degree of alteration was significantly less in CHOP-knockout mice. CHOP deficiency also decreased the I/R-induced activation of caspase-3 and -8, apoptosis, and lipid peroxidation, whereas the activity of endogenous antioxidants increased. In an in vitro I/R model, small interfering RNA targeting CHOP significantly reversed increases in H2O2 formation, inflammatory signals, and apoptotic signals, while enhancing the activity of endogenous antioxidants in renal tubular cells. INNOVATION: To the best of our knowledge, this is the first study which demonstrates that CHOP deficiency attenuates oxidative stress and I/R-induced acute renal injury both in vitro and in vivo. CONCLUSION: These findings suggest that CHOP regulates not only apoptosis-related signaling but also ROS formation and inflammation in renal tubular cells during I/R. CHOP may play an important role in the pathophysiology of I/R-induced renal injury.
AIMS: Renal ischemia-reperfusion (I/R) is a major cause of acute renal failure. The mechanisms of I/R injury include endoplasmic reticulum (ER) stress, inflammatory responses, hypoxia, and generation of reactive oxygen species (ROS). CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) is involved in the ER stress signaling pathways. CHOP is a transcription factor and a major mediator of ER stress-induced apoptosis. However, the role of CHOP in renal I/R injury is still undefined. Here, we investigated whether CHOP could regulate I/R-induced renal injury using CHOP-knockout mice and cultured renal tubular cells as models. RESULTS: In CHOP-knockout mice, loss of renal function induced by I/R was prevented. Renal proximal tubule damage was induced by I/R in wild-type mice; however, the degree of alteration was significantly less in CHOP-knockout mice. CHOP deficiency also decreased the I/R-induced activation of caspase-3 and -8, apoptosis, and lipid peroxidation, whereas the activity of endogenous antioxidants increased. In an in vitro I/R model, small interfering RNA targeting CHOP significantly reversed increases in H2O2 formation, inflammatory signals, and apoptotic signals, while enhancing the activity of endogenous antioxidants in renal tubular cells. INNOVATION: To the best of our knowledge, this is the first study which demonstrates that CHOP deficiency attenuates oxidative stress and I/R-induced acute renal injury both in vitro and in vivo. CONCLUSION: These findings suggest that CHOP regulates not only apoptosis-related signaling but also ROS formation and inflammation in renal tubular cells during I/R. CHOP may play an important role in the pathophysiology of I/R-induced renal injury.
Authors: Nanhu Quan; Lin Wang; Xu Chen; Chelsea Luckett; Courtney Cates; Thomas Rousselle; Yang Zheng; Ji Li Journal: J Mol Cell Cardiol Date: 2018-01-08 Impact factor: 5.000