Genetic engineering of glomerular sclerosis in the mouse via control of onset and severity of podocyte-specific injury
Genetic engineering of glomerular sclerosis in the mouse via control of onset and severity of podocyte-specific injury
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DOI：
10.1681/asn.2004080720
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发表时间：
2005-04-01
影响因子：
13.6
通讯作者：
Ichikawa, I
中科院分区：
文献类型：
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作者：
Matsusaka, T;Xin, J;Ichikawa, I
本研究旨在建立获得性肾小球硬化的小鼠模型。设计了一种模型系统，其允许以可以控制发作和严重程度的方式诱导足细胞损伤。首先产生在足细胞中选择性表达人CD 25的转基因小鼠品系（NEP 25）。注射抗Tac（Fv）-PE 38（LMB 2），一种与人CD 25特异性结合的免疫毒素，可诱导NEP 25小鼠进行性非选择性蛋白尿、腹水和水肿。足细胞表现为足突消失、空泡变性、脱落和突触足蛋白、WT-1、nephrin和podocalyxin的下调。系膜细胞表现为基质扩张，胶原增加，系膜溶解，随后硬化。壁上皮细胞空泡变性、增生，内皮细胞肿胀。肾小球损伤的严重程度是LMB 2剂量依赖性的。在1.25 ng/g体重或更高时，NEP 25小鼠发生进行性肾小球损伤，并在2周内死亡。用0.625 ng/g体重的LMB 2，NEP 25小鼠存活> 4周并发展局灶节段性肾小球硬化。因此，该研究建立了获得性进行性肾小球硬化的小鼠模型，其中发作和严重程度可以通过实验操作预先编程。
This study aimed to generate a mouse model of acquired glomerular sclerosis. A model system that allows induction of podocyte injury in a manner in which onset and severity can be controlled was designed. A transgenic mouse strain (NEP25) that expresses human CD25 selectively in podocytes was first generated. Injection of anti-Tac (Fv)-PE38 (LMB2), an immunotoxin with specific binding to human CD25, induced progressive nonselective proteinuria, ascites, and edema in NEP25 mice. Podocytes showed foot process effacement, vacuolar degeneration, detachment and downregulation of synaptopodin, WT-1, nephrin, and podocalyxin. Mesangial cells showed matrix expansion, increased collagen, mesangiolysis, and, later, sclerosis. Parietal epithelial cells showed vacuolar degeneration and proliferation, whereas endothelial cells were swollen. The severity of the glomerular injury was LMB2 dose dependent. With 1.25 ng/g body wt or more, NEP25 mice developed progressive glomerular damage and died within 2 wk. With 0.625 ng/g body wt of LMB2, NEP25 mice survived > 4 wk and developed focal segmental glomerular sclerosis. Thus, the study has established a mouse model of acquired progressive glomerular sclerosis in which onset and severity can be preprogrammed by experimental maneuvers.