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Bohnert, B.N. ; Menacher, M.* ; Janessa, A.* ; Wörn, M.* ; Schork, A. ; Daiminger, S.* ; Kalbacher, H.* ; Häring, H.-U. ; Daniel, C.* ; Amann, K.* ; Sure, F.* ; Bertog, M.* ; Haerteis, S.* ; Korbmacher, C.* ; Artunc, F.

Aprotinin prevents proteolytic epithelial sodium channel (ENaC) activation and volume retention in nephrotic syndrome.

Kidney Int. 93, 159-172 (2017)
Postprint DOI
Open Access Green
Volume retention in nephrotic syndrome has been linked to activation of the epithelial sodium channel (ENaC) by proteolysis of its γ-subunit following urinary excretion of serine proteases such as plasmin. Here we tested whether pharmacological inhibition of urinary serine protease activity might protect from ENaC activation and volume retention in nephrotic syndrome. Urine from both nephrotic mice (induced by doxorubicin injection) and nephrotic patients exhibited high aprotinin-sensitive serine protease activity. Treatment of nephrotic mice with the serine protease inhibitor aprotinin by means of subcutaneous sustained-release pellets normalized urinary serine protease activity and prevented sodium retention, as did treatment with the ENaC inhibitor amiloride. In the kidney cortex from nephrotic mice, immunofluorescence revealed increased apical γ-ENaC staining, normalized by aprotinin treatment. In Xenopus laevis oocytes heterologously expressing murine ENaC, aprotinin had no direct inhibitory effect on channel activity but prevented proteolytic channel activation. Thus, our study shows that volume retention in experimental nephrotic syndrome is related to proteolytic ENaC activation by proteasuria and can be prevented by treatment with aprotinin. Hence, inhibition of urinary serine protease activity might become a therapeutic approach to treat patients with nephrotic-range proteinuria.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Enac ; Aprotinin ; Mice ; Nephrotic Syndrome ; Protease Inhibitor ; Proteolysis ; Proteolytic Channel Activation ; Serine Protease; Inducible Kinase 1; Collecting Duct; Serine Proteases; In-vivo; Increased Expression; Cardiac-surgery; Cleavage Sites; Gamma-subunit; Na+ Channels; Mouse Model
ISSN (print) / ISBN 0085-2538
e-ISSN 1523-1755
Zeitschrift Kidney International
Quellenangaben Band: 93, Heft: 1, Seiten: 159-172 Artikelnummer: , Supplement: ,
Verlag Nature Publishing Group
Verlagsort New York
Begutachtungsstatus Peer reviewed