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

Acta Physiologica
Silke HaerteisFerruh Artunc

Abstract

Recent 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. We 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. In patients with CKD, we found that PKLK is excreted in the urine up to a concentration of 2 μg mL-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 67 kDa γ-ENaC cleavage product at the cell surface consistent with proteolytic activation. Mutating a putative prostasin cleavage site in γ-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. Howe...Continue Reading

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Citations

Jul 14, 2018·Proteomics·Beatriz MagalhãesRui Vitorino
Jan 1, 2019·Acta Physiologica·Ferruh ArtuncBernhard N Bohnert
Dec 4, 2019·Current Opinion in Nephrology and Hypertension·Gitte R HinrichsPer Svenningsen
Jan 18, 2020·Acta Physiologica·Philipp Hillmeister, Anja Bondke Persson
Dec 4, 2019·Acta Physiologica·Bernhard N BohnertFerruh Artunc
Feb 2, 2021·American Journal of Physiology. Renal Physiology·Gustavo FrindtLawrence G Palmer
Oct 17, 2020·Acta Physiologica·Ralf Mrowka
Aug 24, 2021·American Journal of Physiology. Renal Physiology·Bernhard N BohnertFerruh Artunc

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