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Kidney Int. 2018 Jan;93(1):159-172. doi: 10.1016/j.kint.2017.07.023. Epub 2017 Oct 14.

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

Author information

1
Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the Eberhards Karls University of Tuebingen, Tübingen, Germany; German Center for Diabetes Research (DZD) at the Eberhards Karls University of Tuebingen, Tübingen, Germany.
2
Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany.
3
Interfaculty Institute of Biochemistry, Eberhards Karls University of Tuebingen, Tübingen, Germany.
4
Institute of Pathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany.
5
Institute of Cellular and Molecular Physiology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany.
6
Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the Eberhards Karls University of Tuebingen, Tübingen, Germany; German Center for Diabetes Research (DZD) at the Eberhards Karls University of Tuebingen, Tübingen, Germany. Electronic address: ferruh.artunc@med.uni-tuebingen.de.

Abstract

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.

KEYWORDS:

ENaC; aprotinin; mice; nephrotic syndrome; protease inhibitor; proteolysis; proteolytic channel activation; serine protease

PMID:
29042083
DOI:
10.1016/j.kint.2017.07.023
[Indexed for MEDLINE]

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