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Wörner, S.* ; Bohnert, B.N. ; Wörn, M.* ; Xiao, M.* ; Janessa, A.* ; Birkenfeld, A.L. ; Amann, K.* ; Daniel, C.* ; Artunc, F.

Renal effects of the serine protease inhibitor aprotinin in healthy conscious mice.

Acta Pharmacol. Sin. 43, 111-120 (2022)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
Treatment with aprotinin, a broad-spectrum serine protease inhibitor with a molecular weight of 6512 Da, was associated with acute kidney injury, which was one of the reasons for withdrawal from the market in 2007. Inhibition of renal serine proteases regulating the epithelial sodium channel ENaC could be a possible mechanism. Herein, we studied the effect of aprotinin in wild-type 129S1/SvImJ mice on sodium handling, tubular function, and integrity under a control and low-salt diet. Mice were studied in metabolic cages, and aprotinin was delivered by subcutaneously implanted sustained release pellets (2 mg/day over 10 days). Mean urinary aprotinin concentration ranged between 642 ± 135 (day 2) and 127 ± 16 (day 8) µg/mL . Aprotinin caused impaired sodium preservation under a low-salt diet while stimulating excessive hyperaldosteronism and unexpectedly, proteolytic activation of ENaC. Aprotinin inhibited proximal tubular function leading to glucosuria and proteinuria. Plasma urea and cystatin C concentration increased significantly under aprotinin treatment. Kidney tissues from aprotinin-treated mice showed accumulation of intracellular aprotinin and expression of the kidney injury molecule 1 (KIM-1). In electron microscopy, electron-dense deposits were observed. There was no evidence for kidney injury in mice treated with a lower aprotinin dose (0.5 mg/day). In conclusion, high doses of aprotinin exert nephrotoxic effects by accumulation in the tubular system of healthy mice, leading to inhibition of proximal tubular function and counterregulatory stimulation of ENaC-mediated sodium transport.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Aprotinin ; Epithelial Sodium Channel ; Renal Dysfunction ; Serine Proteases ; Sodium
ISSN (print) / ISBN 1671-4083
e-ISSN 1745-7254
Zeitschrift Acta Pharmacologica Sinica
Quellenangaben Band: 43, Heft: 1, Seiten: 111-120 Artikelnummer: , Supplement: ,
Verlag Nature Publishing Group
Verlagsort Macmillan Building, 4 Crinan St, London N1 9xw, England
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes Research and Metabolic Diseases (IDM)
Förderungen Projekt DEAL