title: Hydrogen sulfide prevents hydrogen peroxide-induced activation of epithelial sodium channel through a PTEN/PI(3,4,5)P3 dependent pathway.
abstract: Sodium reabsorption through the epithelial sodium channel (ENaC) at the distal segment of the kidney plays an important role in salt-sensitive hypertension. We reported previously that hydrogen peroxide (H2O2) stimulates ENaC in A6 distal nephron cells via elevation of phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) in the apical membrane. Here we report that H2S can antagonize H2O2-induced activation of ENaC in A6 cells. Our cell-attached patch-clamp data show that ENaC open probability (PO ) was significantly increased by exogenous H2O2, which is consistent with our previous finding. The aberrant activation of ENaC induced by exogenous H2O2 was completely abolished by H2S (0.1 mM NaHS). Pre-treatment of A6 cells with H2S slightly decreased ENaC P(O); however, in these cells H2O2 failed to elevate ENaC PO . Confocal microscopy data show that application of exogenous H2O2 to A6 cells significantly increased intracellular reactive oxygen species (ROS) level and induced accumulation of PI(3,4,5)P3 in the apical compartment of the cell membrane. These effects of exogenous H2O2 on intracellular ROS levels and on apical PI(3,4,5)P3 levels were almost completely abolished by treatment of A6 cells with H2S. In addition, H2S significantly inhibited H2O2-induced oxidative inactivation of the tumor suppressor phosphatase and tensin homolog (PTEN) which is a negative regulator of PI(3,4,5)P3. Moreover, BPV(pic), a specific inhibitor of PTEN, elevated PI(3,4,5)P3 and ENaC activity in a manner similar to that of H2O2 in A6 cells. Our data show, for the first time, that H2S prevents H2O2-induced activation of ENaC through a PTEN-PI(3,4,5)P3 dependent pathway.
authors.affiliation: Department of Clinical Pharmacy, the 2nd Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin, PR China.
authors.forename: Jianing
authors.initials: J
authors.lastname: Zhang
authors.forename: Shuo
authors.initials: S
authors.lastname: Chen
authors.forename: Huibin
authors.initials: H
authors.lastname: Liu
authors.forename: Bingkun
authors.initials: B
authors.lastname: Zhang
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhao
authors.forename: Ke
authors.initials: K
authors.lastname: Ma
authors.forename: Dan
authors.initials: D
authors.lastname: Zhao
authors.forename: Qiushi
authors.initials: Q
authors.lastname: Wang
authors.forename: Heping
authors.initials: H
authors.lastname: Ma
authors.forename: Zhiren
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D053503:Epithelial Sodium Channels / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D017136:Ion Transport / Q000187:drug effects; D007686:Kidney Tubules, Distal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009942:Organometallic Compounds / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D012964:Sodium / Q000378:metabolism; D029867:Xenopus Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D004791:Enzyme Inhibitors; D053503:Epithelial Sodium Channels; D009942:Organometallic Compounds; D018129:Phosphatidylinositol Phosphates; D017382:Reactive Oxygen Species; D029867:Xenopus Proteins; C119540:oxodiperoxo(pyridine-2-carboxylate)vanadate(V); C060974:phosphatidylinositol 3,4,5-triphosphate; D012964:Sodium; D006861:Hydrogen Peroxide; C584436:PTEN protein, Xenopus; D010744:Phosphoric Monoester Hydrolases; D006862:Hydrogen Sulfide