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Plasmin in Nephrotic Urine Activates the Epithelial Sodium Channel

Per Svenningsen^*, Claus Bistrup^*,, Ulla G. Friis^*, Marko Bertog, Silke Haerteis, Bettina Krueger, Jane Stubbe^*, Ole Nørregaard Jensen, Helle C. Thiesson^*,, Torben R. Uhrenholt^*, Bente Jespersen^*,, Boye L. Jensen^*, Christoph Korbmacher and Ole Skøtt^*

^* Physiology and Pharmacology, Institute of Medical Biology, University of Southern Denmark, Department of Nephrology Y, Odense University Hospital, Odense C, and Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense M, Denmark; and Department of Cellular and Molecular Physiology, University of Erlangen-Nuremberg, Erlangen, Germany

Correspondence: Dr. Claus Bistrup, Department of Nephrology Y, Odense University Hospital, Sdr. Boulevard 29, DK-5000 Odense C, Denmark. Phone: +4565411762; Fax: +4565413452; E-mail: claus.bistrup{at}ouh.regionsyddanmark.dk

Received for publication April 8, 2008. Accepted for publication September 2, 2008.

Proteinuria and increased renal reabsorption of NaCl characterize the nephrotic syndrome. Here, we show that protein-rich urine from nephrotic rats and from patients with nephrotic syndrome activate the epithelial sodium channel (ENaC) in cultured M-1 mouse collecting duct cells and in Xenopus laevis oocytes heterologously expressing ENaC. The activation depended on urinary serine protease activity. We identified plasmin as a urinary serine protease by matrix-assisted laser desorption/ionization time of-flight mass spectrometry. Purified plasmin activated ENaC currents, and inhibitors of plasmin abolished urinary protease activity and the ability to activate ENaC. In nephrotic syndrome, tubular urokinase-type plasminogen activator likely converts filtered plasminogen to plasmin. Consistent with this, the combined application of urokinase-type plasminogen activator and plasminogen stimulated amiloride-sensitive transepithelial sodium transport in M-1 cells and increased amiloride-sensitive whole-cell currents in Xenopus laevis oocytes heterologously expressing ENaC. Activation of ENaC by plasmin involved cleavage and release of an inhibitory peptide from the ENaC subunit ectodomain. These data suggest that a defective glomerular filtration barrier allows passage of proteolytic enzymes that have the ability to activate ENaC.

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