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Sodium retention by uPA-plasmin-ENaC in nephrotic syndrome - Authors reply There is a great interest in exploring the mechanisms of oedema in nephrotic syndrome (NS) as evidenced by two parallel studies published in Acta Physiologica.[[1]] This has generated an editorial comment[3] which we respond to by this rebuttal. This seminal observation indicates that serine protease activity contributes to nephrotic sodium retention in mouse NS [8]; however, the importance of the individual protease(s) remains to be clarified. [Extracted from the article]

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 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−1/24 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 γENaC. Conclusions: Nephrotic range glomerular proteinuria leads to urokinase‐dependent intratubular plasminogen activation and γENaC cleavage which contribute to sodium accumulation. [ABSTRACT FROM AUTHOR]