title: Physiological regulation of epithelial sodium channel by proteolysis.
abstract: OBJECTIVE
  Activation of epithelial sodium channel (ENaC) by proteolysis appears to be relevant for day-to-day physiological regulation of channel activity in kidney and other epithelial tissues. Pathophysiogical, proteolytic activation of ENaC in kidney has been demonstrated in proteinuric disease.
  
  
  RESULTS
  A variation in sodium and potassium intake or plasma aldosterone changes the number of cleaved α and γ-ENaC subunits and is associated with changes in ENaC currents. The protease furin mediates intracellular cleavage, whereas the channel-activating protease prostasin (CAP-1), which is glycophosphatidylinositol-anchored to the apical cell surface, mediates important extracellular cleavage. Soluble protease activity is very low in urine under physiological conditions but rises in proteinuria. In nephrotic syndrome, the dominant soluble protease activity is plasmin, which is formed from filtered plasminogen via urokinase-type plasminogen activator. Plasmin activates ENaC directly at high concentrations and through prostasin at lower concentrations.
  
  
  CONCLUSIONS
  The discovery of serine protease-mediated activation of renal ENaC in physiological and pathophysiological conditions opens the way for new understanding of the pathogenesis of proteinuric sodium retention, which may involve plasmin and present several potential new drug targets.
authors.affiliation: Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, and Department of Nephrology Y, Odense University Hospital, Odense, Denmark.
authors.forename: Per
authors.initials: P
authors.lastname: Svenningsen
authors.forename: Ulla G
authors.initials: UG
authors.lastname: Friis
authors.forename: Claus
authors.initials: C
authors.lastname: Bistrup
authors.forename: Kristian B
authors.initials: KB
authors.lastname: Buhl
authors.forename: Boye L
authors.initials: BL
authors.lastname: Jensen
authors.forename: Ole
authors.initials: O
authors.lastname: Skøtt
mesh_terms: D000450:Aldosterone / Q000378:metabolism; D000818:Animals; D004847:Epithelial Cells / Q000201:enzymology*; D053503:Epithelial Sodium Channels / Q000378:metabolism*; D006801:Humans; D015640:Ion Channel Gating; D017136:Ion Transport; D007684:Kidney Tubules / Q000201:enzymology* / Q000503:physiopathology; D010447:Peptide Hydrolases / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism; D011507:Proteinuria / Q000201:enzymology / Q000503:physiopathology; D012964:Sodium / Q000378:metabolism
chemical_list: D053503:Epithelial Sodium Channels; D000450:Aldosterone; D012964:Sodium; D010447:Peptide Hydrolases; D011188:Potassium