Journal
ACTA PHYSIOLOGICA
Volume 227, Issue 4, Pages -Publisher
WILEY
DOI: 10.1111/apha.13362
Keywords
collecting duct; ENaC; nephrotic syndrome; oedema; podocin; proteases
Categories
Funding
- The Novo Nordisk Foundation Funding Source: Medline
- The Danish Society of Nephrology Funding Source: Medline
- The Region of Southern Denmark Funding Source: Medline
- The Faculty of Health Science University of Southern Denmark Funding Source: Medline
- The Strategic Research Council/Innovationsfonden Funding Source: Medline
- Helen and Ejnar Bjørnow's Foundation Funding Source: Medline
- Odense University Hospital Funding Source: Medline
- The Danish Research Council for Independent Research Funding Source: Medline
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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 faeces were collected for 10 days in metabolic cages and analysed for electrolytes, plasminogen, protease activity and ability to activate gamma ENaC 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)/24 h) and compared to controls. Results Twelve days after deletion, podocin-deficient mice developed significant protein and albuminuria associated with increased body wt, 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 the 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 gamma ENaC. Conclusions Nephrotic range glomerular proteinuria leads to urokinase-dependent intratubular plasminogen activation and gamma ENaC cleavage which contribute to sodium accumulation.
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