title: Ischemia/reperfusion-induced CHOP expression promotes apoptosis and impairs renal function recovery: the role of acidosis and GPR4.
abstract: Endoplasmic reticulum (ER) stress-induced apoptosis is implicated in a wide range of diseases, including ischemia/reperfusion injury (IRI). As a common feature of ER stress, the role of CCAT/enhancer-binding protein homologous protein (CHOP) in renal IRI has not been thoroughly investigated. We found that IR led to renal CHOP expression, accompanied by apoptosis induction. Renal IRI was markedly alleviated in CHOP-/- mice. Observations from bone marrow chimeras showed that this was based on CHOP inactivation in renal parenchymal cells rather than inflammatory cells. In vivo and in vitro studies demonstrated that IRI induced CHOP expression in both endothelial and epithelial cells, which was responsible for apoptosis induction. These results were reinforced by the observation that CHOP knockout led to improvement of the postischemic microcirculatory recovery. In vitro studies revealed hypoxia-induced acidosis to be a major inducer of CHOP in endothelial cells, and neutralizing acidosis not only diminished CHOP protein, but also reduced apoptosis. Finally, knockdown of a proton-sensing G protein-coupled receptor GPR4 markedly reduced CHOP expression and endothelial cell apoptosis after hypoxia exposure. These results highlight the importance of hypoxia-acidosis in ER stress signaling regulation in ischemic kidneys and suggest that GPR4 inhibitors or agents targeting CHOP expression may be promising in the treatment of renal IRI.
authors.affiliation: Department of Transplantation and Hepatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China; Department of Urology, First Hospital of Jilin University, Changchun, China.
authors.forename: Biao
authors.initials: B
authors.lastname: Dong
authors.affiliation: Department of Urology, First Hospital of Jilin University, Changchun, China.
authors.forename: Honglan
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Urology, The Affiliated School of Clinical Medicine of Xuzhou Medical College, Xuzhou Central Hospital, Xuzhou, China.
authors.forename: Conghui
authors.initials: C
authors.lastname: Han
authors.affiliation: Animal Facility of Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Jufang
authors.initials: J
authors.lastname: Yao
authors.affiliation: The Central Laboratory of Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Longmei
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Transplantation and Hepatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Urology, First Hospital of Jilin University, Changchun, China.
authors.forename: Yaowen
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Department of Transplantation and Hepatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xia
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000138:Acidosis / Q000150:complications / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016026:Bone Marrow Transplantation; D053148:Caspase 3 / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D055785:Gene Knockdown Techniques; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006851:Hydrochloric Acid / Q000494:pharmacology; D000860:Hypoxia / Q000150:complications / Q000378:metabolism; D007668:Kidney / Q000098:blood supply / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008833:Microcirculation / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D020127:Recovery of Function / Q000187:drug effects; D012039:Regional Blood Flow / Q000187:drug effects; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology*; D051742:Transcription Factor CHOP / Q000378:metabolism*
chemical_list: C517811:GPR4 protein, mouse; D043562:Receptors, G-Protein-Coupled; D051742:Transcription Factor CHOP; D015124:8-Bromo Cyclic Adenosine Monophosphate; D000242:Cyclic AMP; D053148:Caspase 3; D006851:Hydrochloric Acid