Hydrogen Sulfide Prevents Advanced Glycation End-Products Induced Activation of the Epithelial Sodium Channel

Oxid Med Cell Longev. 2015:2015:976848. doi: 10.1155/2015/976848. Epub 2015 May 11.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amitrole / pharmacology
  • Animals
  • Catalase / antagonists & inhibitors
  • Catalase / metabolism
  • Cell Line
  • Chromones / pharmacology
  • Cyclic N-Oxides / pharmacology
  • Epithelial Sodium Channels / metabolism*
  • Glycation End Products, Advanced / toxicity*
  • Microscopy, Confocal
  • Morpholines / pharmacology
  • Nephrons / cytology
  • Oxidative Stress / drug effects*
  • PTEN Phosphohydrolase / antagonists & inhibitors
  • PTEN Phosphohydrolase / metabolism
  • Patch-Clamp Techniques
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects
  • Spin Labels
  • Sulfides / pharmacology*
  • Xenopus
  • Xenopus Proteins / metabolism*


  • Chromones
  • Cyclic N-Oxides
  • Epithelial Sodium Channels
  • Glycation End Products, Advanced
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • Reactive Oxygen Species
  • Spin Labels
  • Sulfides
  • Xenopus Proteins
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Catalase
  • PTEN Phosphohydrolase
  • sodium bisulfide
  • tempol
  • Amitrole