Ischemia/reperfusion-induced CHOP expression promotes apoptosis and impairs renal function recovery: the role of acidosis and GPR4.
Ischemia/reperfusion-induced CHOP expression promotes apoptosis and impairs renal function recovery: the role of acidosis and GPR4.
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缺血/再灌注诱导的 CHOP 表达促进细胞凋亡并损害肾功能恢复：酸中毒和 GPR4 的作用
DOI：
10.1371/journal.pone.0110944
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Xia Q
中科院分区：
文献类型：
--
作者：
Dong B;Zhou H;Han C;Yao J;Xu L;Zhang M;Fu Y;Xia Q
内质网（ER）应激诱导的细胞凋亡涉及广泛的疾病，包括缺血/再灌注损伤（IRI）。作为ER应激的共同特征，CCAT/增强子结合蛋白同源蛋白（CHOP）在肾IRI中的作用尚未得到深入研究。我们发现IR导致肾脏CHOP表达，并伴有细胞凋亡诱导。CHOP−/−小鼠的肾脏IRI明显减轻。对骨髓嵌合体的观察表明，这是基于肾实质细胞而不是炎性细胞中的CHOP失活。体内和体外研究表明，IRI诱导内皮细胞和上皮细胞CHOP表达，这是负责诱导凋亡。CHOP敲除导致缺血后微循环恢复改善的观察结果加强了这些结果。体外研究表明，缺氧诱导的酸中毒是内皮细胞中CHOP的主要诱导物，中和酸中毒不仅减少CHOP蛋白，而且减少凋亡。最后，敲低质子敏感G蛋白偶联受体GPR 4显着降低缺氧暴露后CHOP表达和内皮细胞凋亡。这些结果强调了缺氧-酸中毒在缺血性肾脏ER应激信号调节中的重要性，并表明GPR 4抑制剂或靶向CHOP表达的药物可能在治疗肾IRI中有希望。
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.
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影响因子：
4.8
作者：
Halterman, Marc W.;Gill, Molly;Federoff, Howard J.
通讯作者：
Federoff, Howard J.
影响因子：
3.7
作者：
Zhang S;Han CH;Chen XS;Zhang M;Xu LM;Zhang JJ;Xia Q
通讯作者：
Xia Q
影响因子：
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作者：
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DOI：
10.1152/ajprenal.00117.2013
发表时间：
2014-01-01
影响因子：
4.2
作者：
Yang, Ju-Rong;Yao, Feng-Hua;He, Ya-Ni
通讯作者：
He, Ya-Ni
DOI：
10.1152/ajplung.00166.2010
发表时间：
2011-03-01
影响因子：
4.9
作者：
Lozon, Tricia I.;Eastman, Alison J.;Altemeier, William A.
通讯作者：
Altemeier, William A.