title: AMP-Activated Protein Kinase Attenuates High Salt-Induced Activation of Epithelial Sodium Channels (ENaC) in Human Umbilical Vein Endothelial Cells.
abstract: Recent studies suggest that the epithelial sodium channel (ENaC) is expressed in the endothelial cells. To test whether high salt affects the NO production via regulation of endothelial ENaC, human umbilical vein endothelial cells (HUVECs) were incubated in solutions containing either normal or high sodium (additional 20 mM NaCl). Our data showed that high sodium treatment significantly increased α-, β-, and γ-ENaC expression levels in HUVECs. Using the cell-attached patch-clamp technique, we demonstrated that high sodium treatment significantly increased ENaC open probability (P O ). Moreover, nitric oxide synthase (eNOS) phosphorylation (Ser 1177) levels and NO production were significantly decreased by high sodium in HUVECs; the effects of high sodium on eNOS phosphorylation and NO production were inhibited by a specific ENaC blocker, amiloride. Our results showed that high sodium decreased AMP-activated kinase (AMPK) phosphorylation in endothelial cells. On the other hand, metformin, an AMPK activator, prevented high sodium-induced upregulation of ENaC expression and P O . Moreover, metformin prevented high salt-induced decrease in NO production and eNOS phosphorylation. These results suggest that high sodium stimulates ENaC activation by negatively modulating AMPK activity, thereby leading to reduction in eNOS activity and NO production in endothelial cells.
authors.affiliation: Departments of Cardiology and Clinical Pharmacy, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin 150000, China.
authors.forename: Wei-Wan
authors.identifier: 0000-0001-7659-3429
authors.initials: WW
authors.lastname: Zheng
authors.affiliation: Departments of Cardiology and Clinical Pharmacy, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin 150000, China.
authors.forename: Xin-Yuan
authors.initials: XY
authors.lastname: Li
authors.affiliation: Department of Clinical Pharmacy, Institute of Clinical Pharmacy, The 2nd Affiliated Hospital, Harbin Medical University, Harbin 150086, China.
authors.forename: Hui-Bin
authors.identifier: 0000-0002-9535-3719
authors.initials: HB
authors.lastname: Liu
authors.affiliation: Departments of Cardiology and Clinical Pharmacy, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin 150000, China.
authors.forename: Zi-Rui
authors.identifier: 0000-0002-3301-3225
authors.initials: ZR
authors.lastname: Wang
authors.affiliation: Departments of Cardiology and Clinical Pharmacy, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin 150000, China.
authors.forename: Qing-Qing
authors.initials: QQ
authors.lastname: Hu
authors.affiliation: Departments of Cardiology and Clinical Pharmacy, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin 150000, China.
authors.forename: Yu-Xia
authors.identifier: 0000-0001-7313-0170
authors.initials: YX
authors.lastname: Li
authors.affiliation: Departments of Cardiology and Clinical Pharmacy, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin 150000, China.
authors.forename: Bin-Lin
authors.identifier: 0000-0003-4455-4825
authors.initials: BL
authors.lastname: Song
authors.affiliation: Departments of Cardiology and Clinical Pharmacy, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin 150000, China; Department of Clinical Pharmacy, Institute of Clinical Pharmacy, The 2nd Affiliated Hospital, Harbin Medical University, Harbin 150086, China.
authors.forename: Jie
authors.identifier: 0000-0002-2797-6703
authors.initials: J
authors.lastname: Lou
authors.affiliation: Departments of Cardiology and Clinical Pharmacy, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin 150000, China; Department of Clinical Pharmacy, Institute of Clinical Pharmacy, The 2nd Affiliated Hospital, Harbin Medical University, Harbin 150086, China.
authors.forename: Qiu-Shi
authors.identifier: 0000-0002-4447-9565
authors.initials: QS
authors.lastname: Wang
authors.affiliation: Department of Physiology, Emory University School of Medicine, Atlanta, GA 150040, USA.
authors.forename: He-Ping
authors.initials: HP
authors.lastname: Ma
authors.affiliation: Departments of Cardiology and Clinical Pharmacy, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin 150000, China; Department of Clinical Pharmacy, Institute of Clinical Pharmacy, The 2nd Affiliated Hospital, Harbin Medical University, Harbin 150086, China.
authors.forename: Zhi-Ren
authors.identifier: 0000-0003-1324-6934
authors.initials: ZR
authors.lastname: Zhang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000200:Action Potentials / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D053503:Epithelial Sodium Channels / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008687:Metformin / Q000494:pharmacology; D018613:Microscopy, Confocal; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010766:Phosphorylation / Q000187:drug effects; D021122:Protein Subunits / Q000378:metabolism; D012965:Sodium Chloride / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D053503:Epithelial Sodium Channels; D021122:Protein Subunits; D009569:Nitric Oxide; D012965:Sodium Chloride; D008687:Metformin; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D055372:AMP-Activated Protein Kinases