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

Bohnert BN, Menacher M, Janessa A, Woern M, Schork A, Daiminger S, Kalbacher H, Haering HU, Daniel C, Amann KU, Sure F, Bertog M, Härteis S, Korbmacher C, Artunc F (2018)

Publication Type: Journal article

Publication year: 2018

Journal

Kidney International Nature Publishing Group: Open Access Hybrid Model Option A

Book Volume: 93

Pages Range: 159-172

Journal Issue: 1

DOI: 10.1016/j.kint.2017.07.023

Abstract

Volume retention in nephrotic syndrome has been linked to activation of the epithelial sodium channel (ENaC) by proteolysis of its ?-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 ?-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.

Authors with CRIS profile

Christoph Daniel Department of Nephropathology Kerstin Ute Amann Department of Nephropathology Florian Sure Lehrstuhl für Physiologie (Vegetative Physiologie) Marko Bertog Lehrstuhl für Physiologie (Vegetative Physiologie) Silke Härteis Lehrstuhl für Physiologie (Vegetative Physiologie) Christoph Korbmacher Lehrstuhl für Physiologie (Vegetative Physiologie)

Involved external institutions

Universitätsklinikum Tübingen DE Germany (DE) Eberhard Karls Universität Tübingen DE Germany (DE)

How to cite

APA:

Bohnert, B.N., Menacher, M., Janessa, A., Woern, M., Schork, A., Daiminger, S.,... Artunc, F. (2018). Aprotinin prevents proteolytic epithelial sodium channel (ENaC) activation and volume retention in nephrotic syndrome. Kidney International, 93(1), 159-172. https://doi.org/10.1016/j.kint.2017.07.023

MLA:

Bohnert, Bernhard N., et al. "Aprotinin prevents proteolytic epithelial sodium channel (ENaC) activation and volume retention in nephrotic syndrome." Kidney International 93.1 (2018): 159-172.

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