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Transgenic zebrafish modeling low-molecular-weight proteinuria and lysosomal storage diseases.
Kidney International ( IF 14.8 ) Pub Date : 2019-12-28 , DOI: 10.1016/j.kint.2019.11.016 Zhiyong Chen 1 , Alessandro Luciani 1 , José María Mateos 2 , Gery Barmettler 2 , Rachel H Giles 3 , Stephan C F Neuhauss 4 , Olivier Devuyst 1
Kidney International ( IF 14.8 ) Pub Date : 2019-12-28 , DOI: 10.1016/j.kint.2019.11.016 Zhiyong Chen 1 , Alessandro Luciani 1 , José María Mateos 2 , Gery Barmettler 2 , Rachel H Giles 3 , Stephan C F Neuhauss 4 , Olivier Devuyst 1
Affiliation
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Epithelial cells lining the proximal tubule of the kidney reabsorb and metabolize most of the filtered low-molecular-weight proteins through receptor-mediated endocytosis and lysosomal processing. Congenital and acquired dysfunctions of the proximal tubule are consistently reflected by the inappropriate loss of solutes including low-molecular-weight proteins in the urine. The zebrafish pronephros shares individual functional segments with the human nephron, including lrp2a/megalin-dependent endocytic transport processes of the proximal tubule. Although the zebrafish has been used as a model organism for toxicological studies and drug discovery, there is no available assay that allows large-scale assessment of proximal tubule function in larval or adult stages. Here we establish a transgenic Tg(lfabp::½vdbp-mCherry) zebrafish line expressing in the liver the N-terminal region of vitamin D-binding protein coupled to the acid-insensitive, red monomeric fluorescent protein mCherry (½vdbp-mCherry). This low-molecular-weight protein construct is secreted into the bloodstream, filtered through the glomerulus, reabsorbed by receptor-mediated endocytosis and processed in the lysosomes of proximal tubule cells of the fish. Thus, our proof-of-concept studies using zebrafish larvae knockout for lrp2a and clcn7 or exposed to known nephrotoxins (gentamicin and cisplatin) demonstrate that this transgenic line is useful to monitor low-molecular-weight proteinuria and lysosomal processing. This represents a powerful new model organism for drug screening and studies of nephrotoxicity.
中文翻译：
转基因斑马鱼模拟低分子量蛋白尿和溶酶体贮积病。
肾近端小管内衬的上皮细胞通过受体介导的内吞作用和溶酶体加工过程重新吸收并代谢了大部分过滤的低分子量蛋白质。尿液中包括低分子量蛋白质在内的溶质的不适当流失始终反映出近端小管的先天性和获得性功能障碍。斑马鱼前肾与人肾单位共享各个功能部分，包括近端小管的lrp2a / megalin依赖性内吞转运过程。尽管斑马鱼已被用作毒理学研究和药物发现的模型生物，但尚无可用于大规模评估幼虫或成年阶段近端肾小管功能的测定方法。在这里，我们建立了转基因Tg（lfabp :: ½vdbp-mCherry）斑马鱼品系，在肝脏中表达与酸性不敏感的红色单体荧光蛋白mCherry（½vdbp-mCherry）偶联的维生素D结合蛋白的N端区域。这种低分子量蛋白质构建体被分泌到血液中，通过肾小球过滤，被受体介导的内吞作用重吸收，并在鱼的近端小管细胞的溶酶体中加工。因此，我们使用斑马鱼幼虫敲除lrp2a和clcn7或暴露于已知肾毒素（庆大霉素和顺铂）的概念验证研究表明，该转基因品系可用于监测低分子量蛋白尿和溶酶体加工。这代表了用于药物筛选和肾毒性研究的强大的新型生物体。
更新日期：2019-12-28
中文翻译：
转基因斑马鱼模拟低分子量蛋白尿和溶酶体贮积病。
肾近端小管内衬的上皮细胞通过受体介导的内吞作用和溶酶体加工过程重新吸收并代谢了大部分过滤的低分子量蛋白质。尿液中包括低分子量蛋白质在内的溶质的不适当流失始终反映出近端小管的先天性和获得性功能障碍。斑马鱼前肾与人肾单位共享各个功能部分，包括近端小管的lrp2a / megalin依赖性内吞转运过程。尽管斑马鱼已被用作毒理学研究和药物发现的模型生物，但尚无可用于大规模评估幼虫或成年阶段近端肾小管功能的测定方法。在这里，我们建立了转基因Tg（lfabp :: ½vdbp-mCherry）斑马鱼品系，在肝脏中表达与酸性不敏感的红色单体荧光蛋白mCherry（½vdbp-mCherry）偶联的维生素D结合蛋白的N端区域。这种低分子量蛋白质构建体被分泌到血液中，通过肾小球过滤，被受体介导的内吞作用重吸收，并在鱼的近端小管细胞的溶酶体中加工。因此，我们使用斑马鱼幼虫敲除lrp2a和clcn7或暴露于已知肾毒素（庆大霉素和顺铂）的概念验证研究表明，该转基因品系可用于监测低分子量蛋白尿和溶酶体加工。这代表了用于药物筛选和肾毒性研究的强大的新型生物体。
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