Liver Kinase B1/AMP-Activated Protein Kinase Pathway Activation Attenuated the Progression of Endotoxemia in the Diabetic Mice
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 dia...
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| Format: | Article |
| Language: | English |
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Cell Physiol Biochem Press GmbH & Co KG
2017-06-01
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| Series: | Cellular Physiology and Biochemistry |
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| Online Access: | http://www.karger.com/Article/FullText/478068 |
| _version_ | 1818172840968454144 |
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| author | Yan Yang Ruolan Dong Danli Hu Zhihui Chen Menglu Fu Dao Wen Wang Xizhen Xu Ling Tu |
| author_facet | Yan Yang Ruolan Dong Danli Hu Zhihui Chen Menglu Fu Dao Wen Wang Xizhen Xu Ling Tu |
| author_sort | Yan Yang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T19:19:01Z |
| format | Article |
| id | doaj.art-92a79d6866a94bee8635ecbd64051b50 |
| institution | Directory Open Access Journal |
| issn | 1015-8987 1421-9778 |
| language | English |
| last_indexed | 2024-12-11T19:19:01Z |
| publishDate | 2017-06-01 |
| publisher | Cell Physiol Biochem Press GmbH & Co KG |
| record_format | Article |
| series | Cellular Physiology and Biochemistry |
| spelling | doaj.art-92a79d6866a94bee8635ecbd64051b502022-12-22T00:53:35ZengCell Physiol Biochem Press GmbH & Co KGCellular Physiology and Biochemistry1015-89871421-97782017-06-0142276177910.1159/000478068478068Liver Kinase B1/AMP-Activated Protein Kinase Pathway Activation Attenuated the Progression of Endotoxemia in the Diabetic MiceYan YangRuolan DongDanli HuZhihui ChenMenglu FuDao Wen WangXizhen XuLing TuBackground/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.http://www.karger.com/Article/FullText/478068Diabetes mellitusEndotoxemiaAMP-activated protein kinaseInflammatory responseLPSEndothelial permeability |
| spellingShingle | Yan Yang Ruolan Dong Danli Hu Zhihui Chen Menglu Fu Dao Wen Wang Xizhen Xu Ling Tu Liver Kinase B1/AMP-Activated Protein Kinase Pathway Activation Attenuated the Progression of Endotoxemia in the Diabetic Mice Cellular Physiology and Biochemistry Diabetes mellitus Endotoxemia AMP-activated protein kinase Inflammatory response LPS Endothelial permeability |
| title | Liver Kinase B1/AMP-Activated Protein Kinase Pathway Activation Attenuated the Progression of Endotoxemia in the Diabetic Mice |
| title_full | Liver Kinase B1/AMP-Activated Protein Kinase Pathway Activation Attenuated the Progression of Endotoxemia in the Diabetic Mice |
| title_fullStr | Liver Kinase B1/AMP-Activated Protein Kinase Pathway Activation Attenuated the Progression of Endotoxemia in the Diabetic Mice |
| title_full_unstemmed | Liver Kinase B1/AMP-Activated Protein Kinase Pathway Activation Attenuated the Progression of Endotoxemia in the Diabetic Mice |
| title_short | Liver Kinase B1/AMP-Activated Protein Kinase Pathway Activation Attenuated the Progression of Endotoxemia in the Diabetic Mice |
| title_sort | liver kinase b1 amp activated protein kinase pathway activation attenuated the progression of endotoxemia in the diabetic mice |
| topic | Diabetes mellitus Endotoxemia AMP-activated protein kinase Inflammatory response LPS Endothelial permeability |
| url | http://www.karger.com/Article/FullText/478068 |
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