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

作　　者：Stefan Wörner Bernhard N.Bohnert Matthias Wörn Mengyun Xiao Andrea Janessa Andreas L.Birkenfeld Kerstin Amann Christoph Daniel Ferruh Artunc 

机构地区：[1]Division of Endocrinology,Diabetology and Nephrology,Department of Internal Medicine,University Hospital Tübingen,Tübingen,Germany [2]Institute of Diabetes Research and Metabolic Diseases(IDM)of the Helmholtz Center Munich at the University Tübingen,Tübingen,Germany [3]German Center for Diabetes Research(DZD)at the University Tübingen,Tübingen,Germany [4]Department of Nephropathology,Friedrich-Alexander University(FAU)Erlangen-Nürnberg(FAU),Erlangen,Germany

出　　处：《Acta Pharmacologica Sinica》2022年第1期111-120,共10页中国药理学报（英文版）

基　　金：This study was supported by grants from the Deutsche Forschungsgemeinschaft(DFG,German Research Foundation)to FA(AR 1092/2-2)and to KA/CD(SFB 1350,project number 387509280).

摘　　要：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.

关 键 词：APROTININ serine proteases renal dysfunction epithelial sodium channel SODIUM 

分 类 号：R692[医药卫生—泌尿科学] R96[医药卫生—外科学]