Kidney international, 2018-01, Vol.93 (1), p.159-172
2018
Details
- Autor(en) / Beteiligte
- Titel
- Aprotinin prevents proteolytic epithelial sodium channel (ENaC) activation and volume retention in nephrotic syndrome
- Ist Teil von
- Kidney international, 2018-01, Vol.93 (1), p.159-172
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2018
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0085-2538eISSN: 1523-1755DOI: 10.1016/j.kint.2017.07.023Titel-ID: cdi_proquest_miscellaneous_1952526770
- Format
- –
- Schlagworte
- Animals, aprotinin, Aprotinin - pharmacology, Case-Control Studies, Disease Models, Animal, Doxorubicin, Edema - drug therapy, Edema - enzymology, Edema - etiology, Edema - physiopathology, ENaC, Epithelial Sodium Channels - drug effects, Epithelial Sodium Channels - genetics, Epithelial Sodium Channels - metabolism, Humans, Ion Channel Gating - drug effects, Kidney - drug effects, Kidney - metabolism, Kidney - pathology, mice, Mice, 129 Strain, nephrotic syndrome, Nephrotic Syndrome - chemically induced, Nephrotic Syndrome - drug therapy, Nephrotic Syndrome - enzymology, Nephrotic Syndrome - physiopathology, protease inhibitor, Proteolysis, proteolytic channel activation, serine protease, Serine Proteases - urine, Serine Proteinase Inhibitors - pharmacology, Signal Transduction - drug effects, Water-Electrolyte Balance - drug effects, Xenopus laevis