Urokinase-type plasminogen activator contributes to amiloride-sensitive sodium retention in nephrotic range glomerular proteinuria in mice

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DOI

  • Gitte R Hinrichs, Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
  • ,
  • Kathrin Weyer
  • Ulla G Friis, Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
  • ,
  • Per Svenningsen, Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
  • ,
  • Ida Katrine Lund, Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
  • ,
  • Rikke Nielsen
  • Géraldine Mollet, Inserm U1163, Imagine Institute, Laboratory of Hereditary Kidney Diseases, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Paris, France.
  • ,
  • Corinne Antignac, Inserm U1163, Imagine Institute, Laboratory of Hereditary Kidney Diseases, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Paris, France; Department of Genetics, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
  • ,
  • Claus Bistrup, Department of Endocrinology, Odense University Hospital, Odense, Denmark ; Department of Gynecology and Obstetrics, Odense University Hospital, Odense, Denmark ; Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.
  • ,
  • Boye L Jensen, Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
  • ,
  • Henrik Birn

AIM: Activation of sodium reabsorption by urinary proteases has been implicated in sodium retention associated with nephrotic syndrome. The study was designed to test the hypothesis that nephrotic proteinuria in mice after conditional deletion of podocin leads to urokinase dependent, amiloride-sensitive plasmin-mediated sodium and water retention.

METHODS: Ten days after podocin knockout, urine and feces was collected for 10 days in metabolic cages and analysed for electrolytes, plasminogen, protease activity, and ability to activate γENaC by patch clamp and western blot. Mice were treated with amiloride (2.5 mg-kg-1 for 2 days and 10 mg-kg-1 for 2 days) or an anti-urokinase-type plasminogen activator (uPA) targeting antibody (120 mg-kg-1 /24h) and compared to controls.

RESULTS: Twelve days after deletion, podocin-deficient mice developed significant protein-and albuminuria associated with increased body weight, ascites, sodium accumulation, and suppressed plasma renin. This was associated with increased urinary excretion of plasmin and plasminogen that correlated with albumin excretion, urine protease activity co-migrating with active plasmin, and ability of urine to induce an amiloride-sensitive inward current in M1 cells in vitro. Amiloride treatment in podocin-deficient mice resulted in weight loss, increased sodium excretion, normalization of sodium balance and prevention of the activation of plasminogen to plasmin in urine in a reversible way. Administration of uPA targeting antibody abolished urine activation of plasminogen, attenuated sodium accumulation and prevented cleavage of γENaC.

CONCLUSIONS: Nephrotic range glomerular proteinuria leads to urokinase dependent intratubular plasminogen activation and γENaC cleavage which contributes to sodium accumulation. This article is protected by copyright. All rights reserved.

Original languageEnglish
Article numbere13362
JournalActa Physiologica (Online)
Volume227
Issue4
Number of pages14
ISSN1748-1716
DOIs
Publication statusPublished - 2019

    Research areas

  • ENaC, collecting duct, nephrotic syndrome, oedema, podocin, proteases

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