胰岛素通过PI3K/AKT及PI3K/ERK通路减轻脂多糖对钠泵α1亚基的抑制

doi:10.12092/j.issn.1009-2501.2019.08.008

中国临床药理学与治疗学 ›› 2019, Vol. 24 ›› Issue (8): 896-902.doi: 10.12092/j.issn.1009-2501.2019.08.008

胰岛素通过PI3K/AKT及PI3K/ERK通路减轻脂多糖对钠泵α1亚基的抑制

刘焕淼¹，陈焯辉²，吴迪¹，黄雪婷¹，万齐全¹

¹中南大学湘雅三医院移植中心监护室，长沙 410013，湖南；²中南大学湘雅医学院，长沙 410083，湖南

收稿日期:2019-04-09 修回日期:2019-06-03 出版日期:2019-08-26 发布日期:2019-08-30
通讯作者: 万齐全，男，博士，副主任医师，硕士生导师，研究方向：移植后感染防治、器官功能支持及免疫抑制下的ARDS中LPS对钠泵的影响及机制并药物干预。 Tel：18073157672 E-mail：13548685542@163.com
作者简介:刘焕淼，男，本科，住院医师，研究方向：ARDS中LPS对钠泵的影响及机制并药物干预。 Tel：15173133214 E-mail：lhmxz@126.com

Insulin attenuates the inhibition effect of lipopolysaccharide on Na+-K+-ATPase α1 via PI3K/AKT and PI3K/ERK pathway

LIU Huanmiao¹, CHEN Zhuohui², WU Di¹, HUANG Xueting¹, WAN Qiquan¹

¹ Department of Transplant Surgery, the Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China; ² Xiangya School of Medicine, Central South University, Changsha 410083, Hunan, China

Received:2019-04-09 Revised:2019-06-03 Online:2019-08-26 Published:2019-08-30

摘要/Abstract

摘要：

目的:研究胰岛素减轻脂多糖对肺泡II型上皮细胞Na+-K+-ATPase α1亚基表达抑制的分子机制。方法:以A549细胞为研究对象，脂多糖（1 μg/mL）诱导8 h后，再加用胰岛素（100 nmol/L）处理4 h，采用Western blot法检测Na+-K+-ATPase α1亚基表达及AKT、ERK1/2、p70s6k、NEDD4-2总蛋白表达及其磷酸化水平变化。结果:A549细胞在1 μg/mL脂多糖作用下，Na+-K+-ATPase α1亚基蛋白表达显著降低。胰岛素处理可部分解除脂多糖对A549细胞Na+-K+-ATPase α1亚基表达的抑制。胰岛素上调Na+-K+-ATPase α1亚基表达是通过改变PI3K/AKT及PI3K/ERK通路中关键蛋白AKT、NEDD4-2、ERK1/2、p70s6k的磷酸化水平来实现的。结论:胰岛素通过调控PI3K/AKT及PI3K/ERK通路部分解除脂多糖对肺泡II型上皮细胞Na+-K+-ATPase α1亚基表达的抑制，这为临床上采用胰岛素干预急性呼吸窘迫综合征提供了初步实验依据。

关键词: 胰岛素, 脂多糖, 急性呼吸窘迫综合征, Na+-K+-ATPase α1, PI3K通路

Abstract:

AIM: To investigate the molecular mechanism of insulin alleviating the inhibition of lipopolysaccharide on the expression of Na+-K+-ATPase α1 subunit in pulmonary alveoli type II alveolar cells. METHODS: A549 cells, firstly induced by lipopolysaccharide (1 μg/mL) for 8 hours, were used as the research objects, then treated with insulin (100 nmol/L) for 4 hours. Western blot was used to detect the expression of Na+-K+-ATPase α1 subunit and AKT, ERK1/2, p70s6k, NEDD4-2 total protein expression and changes in their phosphorylation levels. RESULTS:The expression of Na+-K+-ATPase α1 subunit protein was significantly decreased in A549 cells when treated with 1 μg/mL lipopolysaccharide. Insulin treatment could partially relieve the lipopolysaccharide inhibition on the expression of Na+-K+-ATPase α1 subunit in A549 cells. Insulin up-regulation of Na+-K+-ATPase α1 subunit expression was achieved by altering the phosphorylation levels of the key proteins AKT, NEDD4-2, ERK1/2, and p70s6k in the PI3K/AKT and PI3K/ERK pathways.CONCLUSION: Insulin could partially relieve the lipopolysaccharide inhibition on the expression of Na+-K+-ATPase α1 subunit in pulmonary alveoli type II alveolar cells by regulating the PI3K/AKT and PI3K/ERK pathways, which provided a preliminary experimental basis for the clinical use of insulin to intervene in acute respiratory distress syndrome.

Key words: insulin, lipopolysaccharide, acute respiratory distress syndrome, Na+-K+-ATPase α1, PI3K pathway

中图分类号:

R965.2

刘焕淼，陈焯辉，吴迪，黄雪婷，万齐全. 胰岛素通过PI3K/AKT及PI3K/ERK通路减轻脂多糖对钠泵α1亚基的抑制[J]. 中国临床药理学与治疗学, 2019, 24(8): 896-902.

LIU Huanmiao, CHEN Zhuohui, WU Di, HUANG Xueting, WAN Qiquan. Insulin attenuates the inhibition effect of lipopolysaccharide on Na+-K+-ATPase α1 via PI3K/AKT and PI3K/ERK pathway[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2019, 24(8): 896-902.

参考文献

［1］Lin EH, Chang HY, Yeh SD, et al. Polyethyleneimine and DNA nanoparticles-based gene therapy for acute lung injury［J］. Nanomedicine, 2013, 9(8): 1293-1303.
［2］Vadasz I, Sznajder JI. Gas exchange disturbances regulate alveolar fluid clearance during acute lung injury［J］. Front Immunol, 2017, 8: 757.
［3］Huppert LA, Matthay MA. Alveolar fluid clearance in pathologically relevant conditions: in vitro and in vivo models of acute respiratory distress syndrome［J］. Front Immunol, 2017, 8: 371.
［4］Althaus M, Pichl A, Clauss WG, et al. Nitric oxide inhibits highly selective sodium channels and the Na+/K+-ATPase in H441 cells［J］. Am J Respir Cell Mol Biol, 2011, 44(1): 53-65.
［5］Lingrel JB. The physiological significance of the cardiotonic steroid/ouabain-binding site of the Na,K-ATPase［J］. Annu Rev Physiol, 2010, 72: 395-412.
［6］Cicko S, Kohler TC, Ayata CK, et al. Extracellular ATP is a danger signal activating P2X7 receptor in a LPS mediated inflammation (ARDS/ALI)［J］. Oncotarget, 2018, 9(55): 30635-30648.
［7］Leligdowicz A, Chun LF, Jauregui A, et al. Human pulmonary endothelial cell permeability after exposure to LPS-stimulated leukocyte supernatants derived from patients with early sepsis［J］. Am J Physiol Lung Cell Mol Physiol, 2018, 315(5): L638-L644.
［8］Brunkhorst FM, Engel C, Bloos F, et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis［J］. N Engl J Med, 2008, 358(2): 125-139.
［9］Shyamsundar M, Mcauley DF, Ingram RJ, et al. Keratinocyte growth factor promotes epithelial survival and resolution in a human model of lung injury［J］. Am J Respir Crit Care Med, 2014, 189(12): 1520-1529.
［10］Deng W, Li CY, Tong J, et al. Regulation of ENaC-mediated alveolar fluid clearance by insulin via PI3K/Akt pathway in LPS-induced acute lung injury［J］. Respir Res, 2012, 13: 29.
［11］Wagener BM, Roux J, Carles M, et al. Synergistic inhibition of beta2-adrenergic receptor-mediated alveolar epithelial fluid transport by interleukin-8 and transforming growth factor-beta［J］. Anesthesiology, 2015, 122(5): 1084-1092.
［12］Downs CA, Johnson NM, Coca C, et al. Angiotensin II regulates delta-ENaC in human umbilical vein endothelial cells［J］. Microvasc Res, 2018, 116: 26-33.
［13］Qi D, He J, Wang D, et al. 17beta-estradiol suppresses lipopolysaccharide-induced acute lung injury through PI3K/Akt/SGK1 mediated up-regulation of epithelial sodium channel (ENaC) in vivo and in vitro［J］. Respir Res, 2014, 15: 159.
［14］Chen HI, Yeh DY, Liou HL, et al. Insulin attenuates endotoxin-induced acute lung injury in conscious rats［J］. Crit Care Med, 2006, 34(3): 758-764.
［15］He J, Qi D, Wang DX, et al. Insulin upregulates the expression of epithelial sodium channel in vitro and in a mouse model of acute lung injury: role of mTORC2/SGK1 pathway［J］. Exp Cell Res, 2015, 331(1): 164-175.
［16］Zhang W, Wang DX. Study of regulatory effect of insulin on expression of epithelial sodium channel alpha subunit in A549 cells［J］. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue, 2010, 22(7): 385-388.
［17］Qi W, Li H, Cai XH, et al. Lipoxin A4 activates alveolar epithelial sodium channel gamma via the microRNA-21/PTEN/AKT pathway in lipopolysaccharide-induced inflammatory lung injury［J］. Lab Invest, 2015, 95(11): 1258-1268.
［18］Mattes C, Laube M, Thome UH. Rapid elevation of sodium transport through insulin is mediated by AKT in alveolar cells［J］. Physiol Rep, 2014, 2(3): e00269.
［19］Wu K, Tian R, Huang J, et al. Metformin alleviated endotoxemia-induced acute lung injury via restoring AMPK-dependent suppression of mTOR［J］. Chem Biol Interact, 2018, 291: 1-6.
［20］Gille T, Randrianarison-Pellan N, Goolaerts A, et al. Hypoxia-induced inhibition of epithelial Na(+) channels in the lung. Role of Nedd4-2 and the ubiquitin-proteasome pathway［J］. Am J Respir Cell Mol Biol, 2014, 50(3): 526-537.

[1]	廖梦玲, 汪艳, 罗静, 王诺妍, 华玲, 张瑜, 邓非, 袁月, 周军, 周红. 青蒿琥酯抑制巨噬细胞释放前炎症细胞因子的分子作用机制研究[J]. 中国临床药理学与治疗学, 2023, 28(9): 969-978.
[2]	张蕾, 肖兴鹏, 丁煌. 沉默ZKSCAN3基因表达加重脂多糖诱导的小鼠肺损伤[J]. 中国临床药理学与治疗学, 2023, 28(2): 164-170.
[3]	赵世峰, 宋向明, 姚建平. 新型胰高血糖素样肽-1受体/葡萄糖依赖性促胰岛素多肽受体双重激动剂——Tirzepatide[J]. 中国临床药理学与治疗学, 2023, 28(2): 220-227.
[4]	全海燕, 江兴, 何璐. 线粒体自噬在肝胰岛素抵抗中作用机制的研究进展[J]. 中国临床药理学与治疗学, 2022, 27(2): 198-204.
[5]	占珠琴, 白海涛. 不同剂量地塞米松对脓毒症肾损伤大鼠血管紧张素II及其受体、NO水平变化的影响[J]. 中国临床药理学与治疗学, 2021, 26(9): 995-1004.
[6]	王春江，孙伟，孙林丽. 甲巯咪唑致中国人群胰岛素自身免疫综合征的临床特点分析[J]. 中国临床药理学与治疗学, 2020, 25(2): 209-213.
[7]	傅小媚，霍然，邓赛，林潮金，范景皓，王萍，李松沛，秦爱萍，邹明辉，余细勇. 脂多糖刺激的骨髓间充质干细胞来源外泌体改善小鼠心肌梗死后炎症和纤维化[J]. 中国临床药理学与治疗学, 2019, 24(8): 841-851.
[8]	原丽，韩玲娜，常永丽，张翠英. 肠促胰岛素类似物拮抗APP/PS1转基因鼠认知功能损伤的研究[J]. 中国临床药理学与治疗学, 2019, 24(7): 721-729.
[9]	全海燕，刘玉环，杨丽，阳芳，秦旭平. CGRP通过激活cAMP/PPARγ/eNOS途径改善血管内皮细胞胰岛素抵抗[J]. 中国临床药理学与治疗学, 2019, 24(6): 615-622.
[10]	陈燕，朱丽君，方正美，朱汇，金岳龙，沈冲，姚应水. 胰岛素样生长因子1基因多态性与常用抗高血压药物治疗后血压水平的关联研究[J]. 中国临床药理学与治疗学, 2019, 24(2): 171-179.
[11]	丁凡，李文雄，张佳莉，张岩. 糖尿病性肌少症发病机制和治疗靶点的研究进展[J]. 中国临床药理学与治疗学, 2019, 24(12): 1428-1433.
[12]	陈少忠，林梅瑟，程黎民，朱乐乐. 红景天苷注射液对脂多糖诱导脓毒性休克肺损伤大鼠肺血管通透性的影响[J]. 中国临床药理学与治疗学, 2019, 24(11): 1256-1262.
[13]	郑丽，莫娟芬，吴加元，郭丽，鲍轶. 基于网络药理学的虎杖抗高血脂作用及信号通路研究[J]. 中国临床药理学与治疗学, 2019, 24(10): 1107-1119.
[14]	曹迎亚，陈群，王箴，吴敬医，姜小敢，金孝岠，鲁卫华. 巨噬细胞在脂多糖诱导肠上皮细胞凋亡中的作用[J]. 中国临床药理学与治疗学, 2019, 24(10): 1142-1146.
[15]	王艳秋，金岳龙，姚应水，刘凌，朱丽君，常微微，陈燕，郑童，邵姚君. 门冬胰岛素与生物合成人胰岛素治疗妊娠期糖尿病Meta分析[J]. 中国临床药理学与治疗学, 2018, 23(5): 541-546.

胰岛素通过PI3K/AKT及PI3K/ERK通路减轻脂多糖对钠泵α1亚基的抑制

Insulin attenuates the inhibition effect of lipopolysaccharide on Na+-K+-ATPase α1 via PI3K/AKT and PI3K/ERK pathway

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 15

编辑推荐

Metrics

本文评价