Ischemia/reperfusion-induced CHOP expression promotes apoptosis and impairs renal function recovery: the role of acidosis and GPR4.
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 foun...
Main Authors: | , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2014-01-01
|
Series: | PLoS ONE |
Online Access: | http://europepmc.org/articles/PMC4208823?pdf=render |
id |
doaj-5c3b41d6d27e4598b3d071886af44240 |
---|---|
record_format |
Article |
spelling |
doaj-5c3b41d6d27e4598b3d071886af442402020-11-25T00:24:08ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-01910e11094410.1371/journal.pone.0110944Ischemia/reperfusion-induced CHOP expression promotes apoptosis and impairs renal function recovery: the role of acidosis and GPR4.Biao DongHonglan ZhouConghui HanJufang YaoLongmei XuMing ZhangYaowen FuQiang XiaEndoplasmic 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.http://europepmc.org/articles/PMC4208823?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Biao Dong Honglan Zhou Conghui Han Jufang Yao Longmei Xu Ming Zhang Yaowen Fu Qiang Xia |
spellingShingle |
Biao Dong Honglan Zhou Conghui Han Jufang Yao Longmei Xu Ming Zhang Yaowen Fu Qiang Xia Ischemia/reperfusion-induced CHOP expression promotes apoptosis and impairs renal function recovery: the role of acidosis and GPR4. PLoS ONE |
author_facet |
Biao Dong Honglan Zhou Conghui Han Jufang Yao Longmei Xu Ming Zhang Yaowen Fu Qiang Xia |
author_sort |
Biao Dong |
title |
Ischemia/reperfusion-induced CHOP expression promotes apoptosis and impairs renal function recovery: the role of acidosis and GPR4. |
title_short |
Ischemia/reperfusion-induced CHOP expression promotes apoptosis and impairs renal function recovery: the role of acidosis and GPR4. |
title_full |
Ischemia/reperfusion-induced CHOP expression promotes apoptosis and impairs renal function recovery: the role of acidosis and GPR4. |
title_fullStr |
Ischemia/reperfusion-induced CHOP expression promotes apoptosis and impairs renal function recovery: the role of acidosis and GPR4. |
title_full_unstemmed |
Ischemia/reperfusion-induced CHOP expression promotes apoptosis and impairs renal function recovery: the role of acidosis and GPR4. |
title_sort |
ischemia/reperfusion-induced chop expression promotes apoptosis and impairs renal function recovery: the role of acidosis and gpr4. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2014-01-01 |
description |
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. |
url |
http://europepmc.org/articles/PMC4208823?pdf=render |
work_keys_str_mv |
AT biaodong ischemiareperfusioninducedchopexpressionpromotesapoptosisandimpairsrenalfunctionrecoverytheroleofacidosisandgpr4 AT honglanzhou ischemiareperfusioninducedchopexpressionpromotesapoptosisandimpairsrenalfunctionrecoverytheroleofacidosisandgpr4 AT conghuihan ischemiareperfusioninducedchopexpressionpromotesapoptosisandimpairsrenalfunctionrecoverytheroleofacidosisandgpr4 AT jufangyao ischemiareperfusioninducedchopexpressionpromotesapoptosisandimpairsrenalfunctionrecoverytheroleofacidosisandgpr4 AT longmeixu ischemiareperfusioninducedchopexpressionpromotesapoptosisandimpairsrenalfunctionrecoverytheroleofacidosisandgpr4 AT mingzhang ischemiareperfusioninducedchopexpressionpromotesapoptosisandimpairsrenalfunctionrecoverytheroleofacidosisandgpr4 AT yaowenfu ischemiareperfusioninducedchopexpressionpromotesapoptosisandimpairsrenalfunctionrecoverytheroleofacidosisandgpr4 AT qiangxia ischemiareperfusioninducedchopexpressionpromotesapoptosisandimpairsrenalfunctionrecoverytheroleofacidosisandgpr4 |
_version_ |
1725353895671103488 |