Liver Kinase B1/AMP-Activated Protein Kinase Pathway Activation Attenuated the Progression of Endotoxemia in the Diabetic Mice
Liver Kinase B1/AMP-Activated Protein Kinase Pathway Activation Attenuated the Progression of Endotoxemia in the Diabetic Mice
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DOI：
10.1159/000478068
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发表时间：
2017-06
影响因子：
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通讯作者：
Yan Yang;Ruolan Dong;D. Hu;Zhi-hui Chen;M. Fu;Daowen Wang;Xizhen Xu;L. Tu
中科院分区：
文献类型：
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作者：
Yan Yang;Ruolan Dong;D. Hu;Zhi-hui Chen;M. Fu;Daowen Wang;Xizhen Xu;L. Tu
背景/目的：脓毒症是一种在全球范围内发病率持续上升的常见疾病，糖尿病可能会使情况变得更糟。本研究旨在探讨LKB1/AMPK信号通路在糖尿病合并全身性内毒素血症中的作用。方法：采用链脲佐菌素诱导的糖尿病小鼠(STZ-小鼠)和db/db糖尿病小鼠，观察LKB1/AMPK信号通路激活对内毒素血症的影响。以高糖和内毒素同时刺激原代培养的腹膜巨噬细胞和人脐静脉内皮细胞(HUVECs)单层，探讨其可能的分子机制。结果：内毒素、高糖或同时给予高糖后，HUVECs、巨噬细胞和肺组织中磷酸化AMPK的表达均下降，二甲双胍激活AMPK后，HUVECs、巨噬细胞和肺组织中磷酸化AMPK的表达下降。此外，内毒素和高糖联合处理通过增强氧化应激反应降低了LKB1和磷酸化AMPK的表达，更重要的是，腺病毒介导的LKB1过表达抑制了巨噬细胞和HUVECs磷酸化AMPK的表达。二甲双胍激活AMPK可改善STZ诱导的糖尿病小鼠和db/db糖尿病小鼠的存活率，这与降低肺内皮细胞高通透性和全身炎症反应有关。此外，AMPK激活也可减轻高糖和内毒素刺激诱导的HUVECs单层通透性，这部分是通过抑制VE-钙粘蛋白的磷酸化来实现的。结论：LKB1/AMPK信号通路激活可提高糖尿病合并内毒素血症小鼠的存活率。因此，LKB1/AMPK信号通路可能成为糖尿病患者严重感染的潜在治疗靶点。
Background/Aims: Sepsis is a common disease that continues to increase in prevalence worldwide, and diabetes mellitus may make the situation worse. This study was designed to determine the role of Liver Kinase B1 (LKB1)/adenosine monophosphate-activated protein kinase (AMPK) signaling pathway in diabetic mice complicated with systemic endotoxemia. Methods: The effects of LKB1/AMPK signaling pathway activation on endotoxemia were investigated in streptozotocin induced diabetic mice (STZ-mice) and db/db diabetic mice. Primary peritoneal macrophages and human umbilical vein endothelial cells (HUVECs) monolayers were simultaneously stimulated by both high glucose and LPS and used as a model to investigate the potential molecular mechanisms in vitro. Results: After treatment with LPS, high glucose or both LPS and high glucose, phosphor-AMPK expression was decreased, and moreover, AMPK activation by metformin treatment alleviated the decrease in phosphor-AMPK expression in HUVECs and macrophages as well as in lung tissue. Furthermore, both LPS and high glucose co-treatment decreased LKB1 and phosphor-AMPK expression via enhanced oxidative stress response, and importantly, LKB1 overexpression mediated by adenovirus inhibited the decrease in phosphor-AMPK expression in macrophages and HUVECs. AMPK activation by metformin administration improved the survival of STZ-induced diabetic mice and db/db diabetic mice, which was associated with reduced lung endothelial hyperpermeability and systemic inflammatory response. Furthermore, the permeability of HUVECs monolayers induced by both high glucose and LPS stimulation was also alleviated by AMPK activation, which was partly via suppression of VE-cadherin phosphorylation. Conclusion: These data demonstrated that LKB1/AMPK signaling pathway activation improved the survival of diabetic mice complicated with endotoxemia. Thus, LKB1/AMPK signaling pathway may serve as a potentially useful therapeutic target for severe infection in diabetic patients.