Dexmedetomidine attenuates lung apoptosis induced by renal ischemia-reperfusion injury through α(2)AR/PI3K/Akt pathway.
Dexmedetomidine attenuates lung apoptosis induced by renal ischemia-reperfusion injury through α(2)AR/PI3K/Akt pathway.
复制标题
右美托咪定通过α(2)AR/PI3K/Akt通路减轻肾缺血再灌注损伤诱导的肺细胞凋亡
DOI：
10.1186/s12967-018-1455-1
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发表时间：
2018-03-23
影响因子：
7.4
通讯作者：
Gu J
中科院分区：
文献类型：
--
作者：
Li J;Chen Q;He X;Alam A;Ning J;Yi B;Lu K;Gu J
肾缺血再灌注引起的急性肺损伤是急性肾损伤相关死亡的主要原因之一。右美托咪定是一种α2肾上腺素能激动剂镇静剂，对急性肾损伤和远端肺损伤有保护作用。我们试图确定右美托咪定是否在急性肾损伤后的急性肺损伤中发挥其抗凋亡作用，以及其常见的抗炎作用，并确定其潜在的机制。在体内，肾缺血60 min（双侧肾蒂闭塞），再灌注24 h，引起急性肾损伤。小鼠在不含α2-肾上腺素能拮抗剂阿替帕唑（250µg/kg, i.p）的情况下给予右美托咪定（25µg/kg, i.p）。采用HE染色对肺组织进行组织学检查，测定动脉血气。采用末端脱氧核苷酸转移酶介导的dUTP缺口末端标记法评估肺细胞凋亡。western blot检测肺组织中caspase 3和p-Akt的表达。体外用假手术或IR后获得的小鼠血清处理C57BL/6J小鼠肺微血管内皮细胞。右美托咪定在细胞血清刺激前给予，单独或与阿替帕唑或LY294002联合给予。cck8法测定细胞活力。采用Hoechst染色、Annexin V-FITC/PI染色、流式细胞术检测细胞凋亡情况。流式细胞术检测线粒体膜电位。western blot检测p-Akt、caspase 3、Bcl-2、Bax的表达。在体内，右美托咪定显著减轻了肺组织的病理改变和细胞凋亡，显著增加了p-Akt的表达。此外，右美托咪定还能轻微改善IR后小鼠的氧合，而阿替帕唑可以消除。在体外，右美托咪定显著抑制IR血清诱导的pmvec活力丧失和凋亡。右美托咪定对PMVECs中p-Akt呈时间和剂量依赖性升高，下调caspase 3和Bax的表达，上调Bcl-2的表达。右美托咪定也能改善MMP的变化。而阿替帕唑或LY294002可消除这些影响。我们的研究结果表明，右美托咪定至少在一定程度上通过α2AR/PI3K/Akt通路减弱了IR诱导的肺细胞凋亡。
Acute lung injury caused by renal ischemia–reperfusion is one of the leading causes of acute kidney injury-related death. Dexmedetomidine, an α2-adrenergic agonist sedative, has been found to have protective effects against acute kidney injury and remote lung injury. We sought to determine whether dexmedetomidine can exert its anti-apoptotic effects in acute lung injury after acute kidney injury, in addition to its common anti-inflammatory effects, and to determine the underlying mechanisms. In vivo, acute kidney injury was induced by 60 min of kidney ischemia (bilateral occlusion of renal pedicles) followed by 24 h of reperfusion. Mice received dexmedetomidine (25 µg/kg, i.p.) in the absence or presence of α2-adrenergic antagonist atipamezole (250 µg/kg, i.p.) before IR. Histological assessment of the lung was conducted by HE staining and arterial blood gases were measured. Lung apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay. The expression of caspase 3 and p-Akt in lung tissue was detected by western blot. In vitro, C57BL/6J mice pulmonary microvascular endothelial cells were treated with serum from mice obtained following sham or IR. Dexmedetomidine was given before serum stimulation in cells, alone or with atipamezole or LY294002. Cell viability was assessed by CCK 8 assay. Cell apoptosis was examined by Hoechst staining and Annexin V-FITC/PI staining flow cytometry analysis. Mitochondrial membrane potential was measured by flow cytometry. The expression of p-Akt, caspase 3, Bcl-2 and Bax was measured by western blot. In vivo, dexmedetomidine remarkably mitigated pathohistological changes and apoptosis and significantly increased p-Akt expression in the lung. In addition, dexmedetomidine also slightly improved oxygenation in mice after IR, which can be abolished by atipamezole. In vitro, dexmedetomidine significantly inhibited IR serum-induced loss of viability and apoptosis in PMVECs. Dexmedetomidine increased p-Akt in a time- and dose-dependent manner, and down-regulated the expression of caspase 3 and Bax and up-regulated the Bcl-2 expression in PMVECs. The changes of MMP were also improved by dexmedetomidine. Whilst these effects were abolished by Atipamezole or LY294002. Our results demonstrated that dexmedetomidine attenuates lung apoptosis induced by IR, at least in part, via α2AR/PI3K/Akt pathway.
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影响因子：
2.3
作者：
Doi, Kent;Ishizu, Tomoko;Noiri, Eisei
通讯作者：
Noiri, Eisei
DOI：
10.1152/ajprenal.90666.2008
发表时间：
2009-07-01
影响因子：
4.2
作者：
Hassoun, Heitham T.;Lie, Mihaela L.;Rabb, Hamid
通讯作者：
Rabb, Hamid
影响因子：
1
作者：
Zang, Dongyu;Shao, Youzhi;Li, Xiaoming
通讯作者：
Li, Xiaoming
影响因子：
0.9
作者：
Yeh, J. -H.;Yang, Y. -C.;Wang, J. -J.
通讯作者：
Wang, J. -J.
影响因子：
3.1
作者：
White, Laura E.;Cui, Yan;Hassoun, Heitham T.
通讯作者：
Hassoun, Heitham T.