Abstract：
Identifying effective drugs for focal segmental glomerulosclerosis (FSGS) treatment holds significant importance. Our high-content drug screening on zebrafish larvae relies on nitroreductase/metronidazole (NTR/MTZ)-induced podocyte ablation to generate FSGS-like injury. A crucial factor for successful drug screenings is minimizing variability in injury induction. For this, we introduce Nifurpirinol (NFP) as a more reliable prodrug for targeted podocyte depletion. NFP showed a 2.3-fold increase in efficiency at concentrations 1600-fold lower compared to MTZ-mediated injury induction. Integration into the screening workflow validated its suitability for the high-content drug screening. The presence of crucial FSGS hallmarks such as podocyte foot process effacement, proteinuria, and activation of parietal epithelial cells, were found. After the isolation of the glomeruli from the larvae, we identified essential pathways by proteomic analysis. This study shows that NFP serves as a highly effective prodrug to induce the FSGS-like disease in zebrafish larvae and is well-suited for a high-content drug screening to identify new candidates for the treatment of FSGS.
摘要：
确定用于局灶性节段肾小球硬化（FSGS）治疗的有效药物具有重要意义。我们对斑马鱼幼虫的高含量药物筛选依赖于硝基还原酶/甲硝唑（NTR/MTZ）诱导的足细胞消融以产生FSGS样损伤。成功进行药物筛选的关键因素是最大程度地减少损伤诱导的变异性。为此，我们引入了Nifurpirinol（NFP）作为靶向足细胞消耗的更可靠的前药。与MTZ介导的损伤诱导相比,NFP在低1600倍的浓度下显示出2.3倍的效率增加。整合到筛选工作流程中验证了其对高含量药物筛选的适用性。关键的FSGS标志的存在，如足细胞足过程消除，蛋白尿,和激活顶叶上皮细胞，被发现了。从幼虫中分离出肾小球后，我们通过蛋白质组学分析确定了基本途径。这项研究表明，NFP作为一种高效的前药在斑马鱼幼虫中诱导FSGS样疾病，非常适合用于高含量药物筛选，以确定治疗FSGS的新候选药物。
