title: Hydrogen Sulfide Prevents Advanced Glycation End-Products Induced Activation of the Epithelial Sodium Channel.
abstract: Advanced glycation end-products (AGEs) are complex and heterogeneous compounds implicated in diabetes. Sodium reabsorption through the epithelial sodium channel (ENaC) at the distal nephron plays an important role in diabetic hypertension. Here, we report that H2S antagonizes AGEs-induced ENaC activation in A6 cells. ENaC open probability (P O ) in A6 cells was significantly increased by exogenous AGEs and that this AGEs-induced ENaC activity was abolished by NaHS (a donor of H2S) and TEMPOL. Incubating A6 cells with the catalase inhibitor 3-aminotriazole (3-AT) mimicked the effects of AGEs on ENaC activity, but did not induce any additive effect. We found that the expression levels of catalase were significantly reduced by AGEs and both AGEs and 3-AT facilitated ROS uptake in A6 cells, which were significantly inhibited by NaHS. The specific PTEN and PI3K inhibitors, BPV(pic) and LY294002, influence ENaC activity in AGEs-pretreated A6 cells. Moreover, after removal of AGEs from AGEs-pretreated A6 cells for 72 hours, ENaC P O remained at a high level, suggesting that an AGEs-related "metabolic memory" may be involved in sodium homeostasis. Our data, for the first time, show that H2S prevents AGEs-induced ENaC activation by targeting the ROS/PI3K/PTEN pathway.
authors.affiliation: Departments of Clinical Pharmacy and Cardiology, Institute of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin 150086, China.
authors.forename: Qiushi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Departments of Clinical Pharmacy and Cardiology, Institute of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin 150086, China.
authors.forename: Binlin
authors.initials: B
authors.lastname: Song
authors.affiliation: Departments of Clinical Pharmacy and Cardiology, Institute of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin 150086, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Jiang
authors.affiliation: Departments of Clinical Pharmacy and Cardiology, Institute of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin 150086, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Liang
authors.affiliation: Departments of Clinical Pharmacy and Cardiology, Institute of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin 150086, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Chen
authors.affiliation: Departments of Clinical Pharmacy and Cardiology, Institute of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin 150086, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Shi
authors.affiliation: Departments of Clinical Pharmacy and Cardiology, Institute of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin 150086, China.
authors.forename: Xinyuan
authors.initials: X
authors.lastname: Li
authors.affiliation: Departments of Clinical Pharmacy and Cardiology, Institute of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin 150086, China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Departments of Clinical Pharmacy and Cardiology, Institute of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin 150086, China.
authors.forename: Mingming
authors.initials: M
authors.lastname: Wu
authors.affiliation: Departments of Clinical Pharmacy and Cardiology, Institute of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin 150086, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Departments of Clinical Pharmacy and Cardiology, Institute of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin 150086, China.
authors.forename: Zhi-Ren
authors.initials: ZR
authors.lastname: Zhang
authors.affiliation: Department of Physiology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: He-Ping
authors.initials: HP
authors.lastname: Ma
mesh_terms: D000640:Amitrole / Q000494:pharmacology; D000818:Animals; D002374:Catalase / Q000037:antagonists & inhibitors / Q000378:metabolism; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D003497:Cyclic N-Oxides / Q000494:pharmacology; D053503:Epithelial Sodium Channels / Q000378:metabolism*; D017127:Glycation End Products, Advanced / Q000633:toxicity*; D018613:Microscopy, Confocal; D009025:Morpholines / Q000494:pharmacology; D009399:Nephrons / Q000166:cytology; D018384:Oxidative Stress / Q000187:drug effects*; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000378:metabolism; D018408:Patch-Clamp Techniques; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013113:Spin Labels; D013440:Sulfides / Q000494:pharmacology*; D014981:Xenopus; D029867:Xenopus Proteins / Q000378:metabolism*
chemical_list: D000640:Amitrole; D002374:Catalase; D002867:Chromones; D003497:Cyclic N-Oxides; D053503:Epithelial Sodium Channels; D017127:Glycation End Products, Advanced; D009025:Morpholines; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017382:Reactive Oxygen Species; D013113:Spin Labels; D013440:Sulfides; D029867:Xenopus Proteins; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C025451:sodium bisulfide; C001803:tempol