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

作者：Bohnert Bernhard N; Menacher Martina; Janessa Andrea; Woern Matthias; Schork Anja; Daiminger Sophie; Kalbacher Hubert; Haering Hans Ulrich; Daniel Christoph; Amann Kerstin; Sure Florian; Bertog Marko; Haerteis Silke; Korbmacher Christoph; Artunc Ferruh^*

来源：Kidney International, 2018, 93(1): 159-172.

DOI：10.1016/j.kint.2017.07.023

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

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

• 出版日期2018-1