医学
氯吡格雷
局灶节段性肾小球硬化
肾脏疾病
肾小球硬化
肾病综合征
药理学
内科学
泌尿科
生物信息学
肾
蛋白尿
生物
阿司匹林
作者
Christoph A. Gebeshuber,Lisa Daniel-Fischer,Heinz Regele,Helga Schachner,Christoph Aufricht,Christoph Kornauth,Matthias Ley,Seth L. Alper,Rebecca Herzog,Klaus Kratochwill,Paul Perco
标识
DOI:10.1016/j.trsl.2023.04.001
摘要
Focal segmental glomerulosclerosis (FSGS) is a glomerular lesion often associated with nephrotic syndrome. It is also associated with a high risk of progression to end-stage kidney disease. Current treatment of FSGS is limited to systemic corticosteroids or calcineurin inhibition, along with inhibitors of the renin-angiotensin-aldosterone system. FSGS is heterogeneous in etiology, and novel therapies targeting specific, dysregulated molecular pathways represent a major unmet medical need. We have generated a network-based molecular model of FSGS pathophysiology using previously established systems biology workflows to allow computational evaluation of compounds for their predicted interference with molecular processes contributing to FSGS. We identified the anti-platelet drug clopidogrel as a therapeutic option to counterbalance dysregulated FSGS pathways. This prediction of our computational screen was validated by testing clopidogrel in the adriamycin FSGS mouse model. Clopidogrel improved key FSGS outcome parameters and significantly reduced urinary albumin to creatinine ratio (P < 0.01) and weight loss (P < 0.01), and ameliorated histopathological damage (P < 0.05). Clopidogrel is used to treat several cardiovascular diseases linked to chronic kidney disease. Clopidogrel's favorable safety profile and its efficacy in the adriamycin mouse FSGS model thus recommend it as an attractive drug repositioning candidate for clinical trial in FSGS.
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