Mechanisms of renal NaCl retention in proteinuric disease

Per Svenningsen, Ulla G Friis, Jostein B Versland, Kristian B Buhl, Britta Frederiksen-Møller, Henrik Andersen, Rikke M Zachar, Claus Bistrup, Ole Skøtt, Jan Stener Jørgensen, René Frydensbjerg Andersen, Boye L Jensen

Research output: Contribution to journalJournal articleResearchpeer-review


In diseases with proteinuria, for example nephrotic syndrome and pre-eclampsia, there often are suppression of plasma renin-angiotensin-aldosterone system components, expansion of extracellular volume and avid renal sodium retention. Mechanisms of sodium retention in proteinuria are reviewed. In animal models of nephrotic syndrome, the amiloride-sensitive epithelial sodium channel ENaC is activated while more proximal renal Na(+) transporters are down-regulated. With suppressed plasma aldosterone concentration and little change in ENaC abundance in nephrotic syndrome, the alternative modality of proteolytic activation of ENaC has been explored. Proteolysis leads to putative release of an inhibitory peptide from the extracellular domain of the gamma ENaC subunit. This leads to full activation of the channel. Plasminogen has been demonstrated in urine from patients with nephrotic syndrome and pre-eclampsia. Urine plasminogen correlates with urine albumin and is activated to plasmin within the urinary space by urokinase-type plasminogen activator. This agrees with aberrant filtration across an injured glomerular barrier independent of the primary disease. Pure plasmin and urine samples containing plasmin activate inward current in single murine collecting duct cells. In this study, it is shown that human lymphocytes may be used to uncover the effect of urine plasmin on amiloride- and aprotinin-sensitive inward currents. Data from hypertensive rat models show that protease inhibitors may attenuate blood pressure. Aberrant filtration of plasminogen and conversion within the urinary space to plasmin may activate gamma ENaC proteolytically and contribute to inappropriate NaCl retention and oedema in acute proteinuric conditions and to hypertension in diseases with chronic microalbuminuria/proteinuria.
Original languageEnglish
JournalActa Physiologica
Issue number3
Pages (from-to)536-545
Publication statusPublished - Mar 2013


  • Animals Blood Pressure Disease Models, Animal Diuretics/therapeutic use Epithelial Sodium Channels/drug effects/*metabolism Fibrinolysin/metabolism Glomerular Filtration Rate Humans Ion Channel Gating Kidney/drug effects/*metabolism/physiopathology Kidney Diseases/drug therapy/*metabolism/physiopathology/urine Proteinuria/drug therapy/*metabolism/physiopathology/urine Renin-Angiotensin System Sodium Chloride, Dietary/*metabolism/urine Water-Electrolyte Balance
  • Hypertension
  • Oedema
  • ENaC
  • Pre-eclampsia
  • Nephrosis
  • Plasmin
  • Proteinuria
  • Blood Pressure
  • Fibrinolysin/metabolism
  • Proteinuria/drug therapy
  • Glomerular Filtration Rate
  • Diuretics/therapeutic use
  • Humans
  • Epithelial Sodium Channels/drug effects
  • Kidney Diseases/drug therapy
  • Sodium Chloride, Dietary/metabolism
  • Kidney/drug effects
  • Animals
  • Renin-Angiotensin System
  • Water-Electrolyte Balance
  • Ion Channel Gating
  • Disease Models, Animal


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