PuSH - Publication Server of Helmholtz Zentrum München: Plasma kallikrein activates the epithelial sodium channel invitro but is not essential for volume retention in nephrotic mice.

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Haerteis, S.* ; Schork, A. ; Doerffel, T.* ; Bohnert, B.N. ; Nacken, R.* ; Woern, M.* ; Xiao, M.* ; Essigke, D.* ; Janessa, A.* ; Schmaier, A.H.* ; Feener, E.P.* ; Häring, H.-U. ; Bertog, M.* ; Korbmacher, C.* ; Artunc, F.

Plasma kallikrein activates the epithelial sodium channel invitro but is not essential for volume retention in nephrotic mice.

Acta Physiol. 224:e13060 (2018)

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AimRecent work has demonstrated that activation of the epithelial sodium channel (ENaC) by aberrantly filtered serine proteases causes sodium retention in nephrotic syndrome. The aim of this study was to elucidate a potential role of plasma kallikrein (PKLK) as a candidate serine protease in this context.MethodsWe analysed PKLK in the urine of patients with chronic kidney disease (CKD, n=171) and investigated its ability to activate human ENaC expressed in Xenopus laevis oocytes. Moreover, we studied sodium retention in PKLK-deficient mice (klkb1(-/-)) with experimental nephrotic syndrome induced by doxorubicin injection.ResultsIn patients with CKD, we found that PKLK is excreted in the urine up to a concentration of 2gmL(-1) which was correlated with albuminuria (r=.71) and overhydration as assessed by bioimpedance spectroscopy (r=.44). PKLK increased ENaC-mediated whole-cell currents, which was associated with the appearance of a 67kDa -ENaC cleavage product at the cell surface consistent with proteolytic activation. Mutating a putative prostasin cleavage site in -ENaC prevented channel stimulation by PKLK. In a mouse model for nephrotic syndrome, active PKLK was present in nephrotic urine of klkb1(+/+) but not of klkb1(-/-) mice. However, klkb1(-/-) mice were not protected from ENaC activation and sodium retention compared to nephrotic klkb1(+/+) mice.ConclusionPlasma kallikrein is detected in the urine of proteinuric patients and mice and activates ENaC invitro involving the putative prostasin cleavage site. However, PKLK is not essential for volume retention in nephrotic mice.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Enac Activation ; Epithelial Sodium Channel ; Plasma Kallikrein ; Proteinuria ; Proteolytic Cleavage ; Sodium Retention; Gamma-subunit; Proteolytic Activation; Plasminogen-activator; Inhibitory Peptide; Serine Proteases; Cleavage Sites; Na+ Channels; Enac; Urokinase; Disease

ISSN (print) / ISBN 1748-1708

e-ISSN 1748-1716

Journal Acta Physiologica

Quellenangaben Volume: 224, Issue: 1, Article Number: e13060

Publisher Wiley

Publishing Place Hoboken

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Diabetes Research and Metabolic Diseases (IDM)