Proteolytic activation of the epithelial sodium channel (ENaC) by factor VII activating protease (FSAP) and its relevance for sodium retention in nephrotic mice.

Autor: Artunc F; Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, University Hospital Tübingen, Tubingen, Germany. ferruh.artunc@med.uni-tuebingen.de.; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University Tübingen, Tubingen, Germany. ferruh.artunc@med.uni-tuebingen.de.; German Center for Diabetes Research (DZD) at the University Tübingen, Tubingen, Germany. ferruh.artunc@med.uni-tuebingen.de., Bohnert BN; Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, University Hospital Tübingen, Tubingen, Germany.; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University Tübingen, Tubingen, Germany.; German Center for Diabetes Research (DZD) at the University Tübingen, Tubingen, Germany., Schneider JC; Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, University Hospital Tübingen, Tubingen, Germany., Staudner T; Institute of Cellular and Molecular Physiology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany., Sure F; Institute of Cellular and Molecular Physiology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany., Ilyaskin AV; Institute of Cellular and Molecular Physiology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany., Wörn M; Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, University Hospital Tübingen, Tubingen, Germany., Essigke D; Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, University Hospital Tübingen, Tubingen, Germany.; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University Tübingen, Tubingen, Germany.; German Center for Diabetes Research (DZD) at the University Tübingen, Tubingen, Germany., Janessa A; Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, University Hospital Tübingen, Tubingen, Germany., Nielsen NV; Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway., Birkenfeld AL; Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, University Hospital Tübingen, Tubingen, Germany.; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University Tübingen, Tubingen, Germany.; German Center for Diabetes Research (DZD) at the University Tübingen, Tubingen, Germany., Etscheid M; Paul Ehrlich Institute, Langen, Germany., Haerteis S; Institute of Cellular and Molecular Physiology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.; Institute of Anatomy, University of Regensburg, Regensburg, Germany., Korbmacher C; Institute of Cellular and Molecular Physiology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany., Kanse SM; Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
Jazyk: angličtina
Zdroj: Pflugers Archiv : European journal of physiology [Pflugers Arch] 2022 Feb; Vol. 474 (2), pp. 217-229. Date of Electronic Publication: 2021 Dec 06.
DOI: 10.1007/s00424-021-02639-7
Abstrakt: Proteolytic activation of the epithelial sodium channel (ENaC) by aberrantly filtered serine proteases is thought to contribute to renal sodium retention in nephrotic syndrome. However, the identity of the responsible proteases remains elusive. This study evaluated factor VII activating protease (FSAP) as a candidate in this context. We analyzed FSAP in the urine of patients with nephrotic syndrome and nephrotic mice and investigated its ability to activate human ENaC expressed in Xenopus laevis oocytes. Moreover, we studied sodium retention in FSAP-deficient mice (Habp2 -/- ) with experimental nephrotic syndrome induced by doxorubicin. In urine samples from nephrotic humans, high concentrations of FSAP were detected both as zymogen and in its active state. Recombinant serine protease domain of FSAP stimulated ENaC-mediated whole-cell currents in a time- and concentration-dependent manner. Mutating the putative prostasin cleavage site in γ-ENaC (γRKRK178AAAA) prevented channel stimulation by the serine protease domain of FSAP. In a mouse model for nephrotic syndrome, active FSAP was present in nephrotic urine of Habp2 +/+ but not of Habp2 -/- mice. However, Habp2 -/- mice were not protected from sodium retention compared to nephrotic Habp2 +/+ mice. Western blot analysis revealed that in nephrotic Habp2 -/- mice, proteolytic cleavage of α- and γ-ENaC was similar to that in nephrotic Habp2 +/+ animals. In conclusion, active FSAP is excreted in the urine of nephrotic patients and mice and activates ENaC in vitro involving the putative prostasin cleavage site of γ-ENaC. However, endogenous FSAP is not essential for sodium retention in nephrotic mice.
(© 2021. The Author(s).)
Databáze: MEDLINE
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