CCAAT-Enhancer-Binding Protein Homologous Protein Deficiency Attenuates Oxidative Stress and Renal Ischemia-Reperfusion Injury

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.