title: Regulation of sodium transport by ENaC in the kidney.
abstract: OBJECTIVE
  The amiloride-sensitive epithelial sodium channel (ENaC) plays a major role in the regulation of sodium transport in the collecting duct and hence sodium balance. This review describes recent findings in the regulation of ENaC function by serine proteases in particular and other regulatory aspects.
  
  
  RESULTS
  Regulation of ENaC occurs at many levels (biophysical, transcriptional, post-translational modifications, assembly, membrane insertion, retrieval, recycling, degradation, etc.). Recent studies have recognized and delineated proteolytic cleavage, particularly of the alpha and gamma subunits, as major mechanisms of activation. Release of peptide fragments from these two subunits appears to be an important aspect of activation. These proteolytic mechanisms of ENaC activation have also been demonstrated in vivo and strongly suggested in clinical circumstances, particularly the nephrotic syndrome. In the nephrotic syndrome, filtered plasminogen may be cleaved by tubular urokinase to yield plasmin which can activate ENaC. In addition to these mechanisms, regulation by ubiquitination and deubiquitination represents a pivotal process. Several important deubiquitinating enzymes have been identified as important in ENaC retention in, or recycling to, the apical membrane. New aspects of the genomic control of ENaC transcription have also been found including histone methylation.
  
  
  CONCLUSIONS
  The mechanisms of regulation of ENaC are increasingly understood to be a complex interplay of many different levels and systems. Proteolytic cleavage of alpha and gamma subunits plays a major role in ENaC activation. This may be particularly clinically relevant in nephrotic syndrome in which plasmin may activate ENaC activity.
authors.affiliation: Departments of Medicine, Physiology and the Tulane Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA. Lhamm@tulane.edu
authors.forename: L Lee
authors.initials: LL
authors.lastname: Hamm
authors.forename: Zhuang
authors.initials: Z
authors.lastname: Feng
authors.forename: Kathleen S
authors.initials: KS
authors.lastname: Hering-Smith
mesh_terms: D000818:Animals; D053503:Epithelial Sodium Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005341:Fibrinolysin / Q000378:metabolism; D006801:Humans; D017136:Ion Transport / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D009404:Nephrotic Syndrome / Q000209:etiology / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D021122:Protein Subunits; D057057:Serine Proteases / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism / Q000494:pharmacology
chemical_list: D053503:Epithelial Sodium Channels; D011480:Protease Inhibitors; D021122:Protein Subunits; D053773:Transforming Growth Factor beta1; D012964:Sodium; D057057:Serine Proteases; D005341:Fibrinolysin