Signaling through hepatocyte vasopressin receptor 1 protects mouse liver from ischemia-reperfusion injury.
Signaling through hepatocyte vasopressin receptor 1 protects mouse liver from ischemia-reperfusion injury.
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通过肝细胞加压素受体 1 发出的信号可保护小鼠肝脏免受缺血再灌注损伤
DOI：
10.18632/oncotarget.12472
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发表时间：
2016-10-25
期刊：
影响因子：
--
通讯作者：
Tao R
中科院分区：
文献类型：
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作者：
Liu X;Luo G;Jiang J;Ma T;Lin X;Jiang L;Cheng J;Tao R
特利加压素已被广泛用于与终末期肝病（ESLD）相关的某些并发症的管理。在我们的初步研究中，特利加压素治疗对失代偿期肝硬化患者的肝功能有有益作用，但它是否在肝脏缺血再灌注损伤（IRI）中发挥作用仍不清楚。使用小鼠非致死性肝IR模型，我们发现特利加压素给药显著改善IR诱导的肝细胞凋亡、坏死和炎症。此外，尽管已知其对内脏血管收缩的作用，IR后小鼠肝组织的血液动力学评价显示特利加压素治疗后总体肝血流量没有变化。进一步的研究发现，肝细胞上的加压素受体1（V1 R）表达上调IR。在离体肝细胞缺氧/复氧模型中，特利加压素的活性成分，赖氨酸加压素，赋予肝细胞抗氧化应激诱导的细胞凋亡。机制研究显示V1 R结合激活Wnt/β-catenin/FoxO 3a/AKT通路，随后绕过促凋亡事件，从而改善肝细胞凋亡。此外，基因敲低V1 R在肝细胞系中的表达或阻断该信号传导途径可消除这种保护作用。结论：这些数据强调了肝细胞V1 R/Wnt/β-catenin/FoxO 3a/AKT通路在保护肝脏免受氧化应激诱导的损伤中的功能重要性。
Terlipressin has been used extensively in the management of certain complications associated with end-stage liver diseases (ESLDs). In our pilot study, terlipressin treatment showed beneficial effects on liver function in patients with decompensated cirrhosis, however whether it plays a role in liver ischemia-reperfusion injury (IRI) remains unknown. Using a mouse nonlethal hepatic IR model, we found terlipressin administration significantly ameliorated IR-induced liver apoptosis, necrosis and inflammation. Furthermore, despite its known effect on visceral vasoconstriction, hemodynamic evaluation of murine hepatic tissue after IR revealed no change of overall hepatic blood flow after terlipressin treatment. Further studies identified the upregulation of vasopressin receptor 1 (V1R) expression on hepatocytes upon IR. In isolated hepatocyte hypoxia/reoxygenation model, the active component of terlipressin, lysine vasopressin, conferred hepatocytes resistant to oxidative stress-induced apoptosis. Mechanistic studies revealed the V1R engagement activated the Wnt/β-catenin/FoxO3a/AKT pathway, which subsequently circumvented the proapoptotic events, thus ameliorated hepatocyte apoptosis. Furthermore, genetic knockdown of V1R expression in hepatocyte cell lines or blockade of this signaling pathway abrogated such protective effect. Conclusion: These data highlight the functional importance of the hepatocyte V1R/Wnt/β-catenin/FoxO3a/AKT pathway in protecting liver from oxidative stress-induced injury.