Takeuchi Kazuhiro, Naito Shokichi, Kawashima Nagako, Ishigaki Naoko, Sano Takashi, Kamata Kouju, Takeuchi Yasuo
Department of Nephrology, Kitasato University School of Medicine, Sagamihara, Japan.
Nephron. 2018;138(1):71-87. doi: 10.1159/000479935. Epub 2017 Sep 30.
Focal segmental glomerulosclerosis (FSGS) is considered a subset of the podocytopathies. The molecular pathogenesis of podocytopathy is still unknown. There has not been an experimental animal model of isolated podocytopathy induced by antibody in C57BL/6 strain, which is widely used as the genetic background. Nephrin is closely associated with the slit diaphragm of the glomerular podocyte, and has recently received attention as a potential therapeutic target. The function of nephrin, especially its role in FSGS development via podocytopathy, is being elucidated. We report our experience with a C57BL/6 FSGS model induced by polyclonal rabbit anti-mouse nephrin antibody (α-mNep Ab).
α-mNep Ab, which was generated by genetic immunization, was administered into C57BL/6 mice at once, intravenously. Urinary protein excretion, the development of glomerulosclerosis and the number of podocyte in mouse kidney were evaluated.
The α-mNep Ab-induced FSGS was associated with massive proteinuria and nephrotic syndrome. In periodic acid-Schiff staining, FSGS was observed from day 7 after antibody injection. Podocyte numbers and podocyte marker (anti-Wilms tumor 1 and anti-synaptopodin)-positive areas were clearly decreased. These results suggest that this FSGS mouse model reliably reproduces the human nephrotic syndrome and FSGS.
We succeeded in making the nephrotic syndrome model mice induced by α-mNep Ab using C57BL/6. This model may be useful for studying the mechanisms of podocytopathy.
局灶节段性肾小球硬化(FSGS)被认为是足细胞病的一个亚型。足细胞病的分子发病机制仍不清楚。在广泛用作遗传背景的C57BL/6品系中,尚未有由抗体诱导的孤立性足细胞病的实验动物模型。Nephrin与肾小球足细胞的裂孔隔膜密切相关,最近作为一个潜在的治疗靶点受到关注。Nephrin的功能,尤其是其在通过足细胞病导致FSGS发展过程中的作用,正在被阐明。我们报告了我们用多克隆兔抗小鼠Nephrin抗体(α-mNep Ab)诱导C57BL/6 FSGS模型的经验。
通过基因免疫产生的α-mNep Ab一次性静脉注射到C57BL/6小鼠体内。评估小鼠尿液蛋白排泄、肾小球硬化的发展以及小鼠肾脏中足细胞的数量。
α-mNep Ab诱导的FSGS与大量蛋白尿和肾病综合征相关。在过碘酸-希夫染色中,抗体注射后第7天观察到FSGS。足细胞数量和足细胞标志物(抗肾母细胞瘤1和抗突触素)阳性区域明显减少。这些结果表明,该FSGS小鼠模型可靠地再现了人类肾病综合征和FSGS。
我们成功地用C57BL/6制作了由α-mNep Ab诱导的肾病综合征模型小鼠。该模型可能有助于研究足细胞病的机制。