Dexmedetomidine attenuates renal ischemia–reperfusion injury through activating PI3K/Akt‐eNOS signaling via α2 adrenoreceptors in renal microvascular endothelial cells
Dexmedetomidine attenuates renal ischemia–reperfusion injury through activating PI3K/Akt‐eNOS signaling via α2 adrenoreceptors in renal microvascular endothelial cells
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DOI：
10.1096/fj.202101626rr
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发表时间：
2022-10
期刊：
影响因子：
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通讯作者：
Xi-Sheng Shan;Jiaxin Zhang;Xiang Wei;Wenhui Tao;Ke Peng;Hua-Yue Liu;Yiqing Wang;Hong Liu
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文献类型：
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作者：
Xi-Sheng Shan;Jiaxin Zhang;Xiang Wei;Wenhui Tao;Ke Peng;Hua-Yue Liu;Yiqing Wang;Hong Liu
肾微血管内皮细胞（Renal microvascular endothelial cells，RMEC）在肾缺血再灌注（ischemia and reperfusion，I/R）损伤过程中起重要作用，与血管反应性的调节和炎症反应的调节密切相关。以往的研究报道了右美托咪定（DEX）对肾I/R损伤的保护作用，但对DEX对RMEC的作用知之甚少。本研究旨在探讨DEX是否通过作用于RMEC减轻肾I/R损伤。小鼠双侧肾动脉阻断45 min后再灌注48 h，培养的RMEC缺氧1 h后复氧24 h。结果表明，DEX在体内减轻了肾I/R损伤，在体外提高了RMEC在H/R损伤期间的细胞活力。基因测序结果显示，PI 3 K/Akt信号通路在肾I/R损伤中处于最高峰，内皮细胞广泛参与肾I/R损伤。DEX激活PI 3 K和Akt的磷酸化，增加eNOS表达，并减弱炎症反应。此外，结果证实了α2肾上腺素受体（α2-AR）在RMEC中的分布。此外，DEX对肾I/R损伤的保护作用被α2-AR拮抗剂（阿替美唑）消除，这被PI 3 K激动剂（740 Y-P）部分逆转。这些结果表明，DEX通过激活RMEC中的PI 3 K/Akt-eNOS通路并通过α2-AR抑制炎症反应来保护肾I/R损伤。
Renal microvascular endothelial cells (RMECs), which are closely related to regulation of vascular reactivity and modulation of inflammation, play a crucial role in the process of renal ischemia and reperfusion (I/R) injury. Previous studies have reported the protective effects of dexmedetomidine (DEX) against renal I/R injury, but little is known about the role of DEX on RMECs. This study aimed to investigate whether DEX alleviated renal I/R injury via acting on the RMECs. Mice underwent bilateral renal artery clamping for 45 min followed by reperfusion for 48 h, and the cultured neonatal mice RMECs were subjected to hypoxia for 1 h followed by reoxygenation (H/R) for 24 h. The results suggest that DEX alleviated renal I/R injury in vivo and improved cell viability of RMECs during H/R injury in vitro. Gene sequencing revealed that the PI3K/Akt was the top enriched signaling pathway and the endothelial cells were widely involved in renal I/R injury. DEX activated phosphorylation of PI3K and Akt, increased eNOS expression, and attenuated inflammatory responses. In addition, the results confirmed the distribution of α2 adrenoreceptor (α2‐AR) in RMECs. Furthermore, the protective effects of DEX against renal I/R injury were abolished by α2‐AR antagonist (atipamezole), which was partly reversed by the PI3K agonist (740 Y‐P). These findings indicated that DEX protects against renal I/R injury by activating the PI3K/Akt‐eNOS pathway and inhibiting inflammation responses via α2‐AR in RMECs.