C/EBP homologous protein (CHOP) gene deficiency attenuates renal ischemia/reperfusion injury in mice

Mi Ra Noh; Jee In Kim; Sang Jun Han; Tae-Jin Lee; Kwon Moo Park

doi:10.1016/j.bbadis.2015.06.004

C/EBP homologous protein (CHOP) gene deficiency attenuates renal ischemia/reperfusion injury in mice

Biochim Biophys Acta. 2015 Sep;1852(9):1895-901. doi: 10.1016/j.bbadis.2015.06.004. Epub 2015 Jun 11.

Authors

Mi Ra Noh¹, Jee In Kim², Sang Jun Han¹, Tae-Jin Lee³, Kwon Moo Park⁴

Affiliations

¹ Department of Anatomy and BK21 Plus, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
² Department of Molecular Medicine and MRC, Keimyung University School of Medicine, Daegu, Republic of Korea.
³ Department of Anatomy, College of Medicine, Yeungnam University, Daegu, Republic of Korea.
⁴ Department of Anatomy and BK21 Plus, Kyungpook National University School of Medicine, Daegu, Republic of Korea. Electronic address: kmpark@knu.ac.kr.

PMID: 26071644
DOI: 10.1016/j.bbadis.2015.06.004

Abstract

C/EBP homologous protein (CHOP), a transcription factor for the expression of apoptosis-related genes, plays an important role in endoplasmic reticulum (ER) stress-related organ diseases, including diseases of the kidney. Here, we investigated the role of CHOP in ischemia/reperfusion (I/R)-induced acute kidney injury using CHOP-knockout (CHOP(-/-)) and wild type (CHOP(+/+)) mice. Fifteen or thirty minutes of bilateral renal ischemia (I/R) insult resulted in necrotic and apoptotic tubular epithelial cell death, together with increases in plasma creatinine (PCr) and blood urea nitrogen (BUN) concentrations. After I/R, BiP/GRP78 and CHOP expressions in the kidney gradually increased over time. CHOP expression was greater in the outer medulla than that in the cortex and localized intensely in the nucleus. I/R caused apoptosis of tubular epithelial cells in both CHOP(-/-) and CHOP(+/+) mice. The number of apoptotic cells after I/R was lower in CHOP(-/-) mice than that in CHOP(+/+) mice. Consistent with the degree of apoptosis, I/R-induced kidney morphological and functional damages were milder in CHOP(-/-) than that in CHOP(+/+) mice. The cleavage of procaspase-3 and the induction of Bax protein after I/R were lower in CHOP(-/-) than that in CHOP(+/+) mice. In contrast, the expression levels of Bcl-2, Bcl-xL, cIAP2, Mcl-1, and XIAP were higher in CHOP(-/-) than that in CHOP(+/+) mice. These results indicate that I/R induces ER stress, leading to the activation of CHOP-associated apoptosis signals, resulting in renal functional and histological damages.

Keywords: Apoptosis; C/EBP homologous protein; CHOP; ER stress; Ischemia.