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Analysis on the mechanism of proteinuria induced by glomerular epithelial cell lesions

肾小球上皮细胞病变引起蛋白尿的机制分析

基本信息

批准号：
13470210
负责人：
SHIMIZU Fujio
金额：
$ 3.71万
依托单位：
NIIGATA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470210/
关键词：
proteinuria glomerular epithelial cell slit membrane nephrin nephrotic syndrome

项目摘要

We have succeeded in cloning the rat homologue of nephrin which is a product of gene responsible for Finnish-type congenital nephrotic syndrome and concluded that proteinuria-inducing monoclonal anti-rat slit membrane antibody 5-1-6 recognizes the extracellular sites of rat nephrin. In 5-1-6 nephropathy, induced by a single injection of 5-1-6, and also in PAN nephrosis, representative rat model for nephrotic syndrome, the expression of nephrin was decreased already in early stage before start of proteinuria, which suggested that the decrease of nephrin expression is not the result but cause of proteinuria and nephrin abnormality is intimately related not only to congenital but also acquired renal lesions, especially the induction of proteinuria.We have succeeded also in cloning the recently reported podocin, a product of gene responsible to familial FSGS. In 5-1-6 nephropathy as well as in PAN nephrosis immunofluorescent positive staining pattern was changed from pseudo-linear to granular just as in the case of nephrin. In 5-1-6 nephropathy podocin was co-localized with nephrin, but not in PAN nephropathy. The decrease in the expression of podocin at the mRNA level was recognized in 5-1-6 nephropathy.In conclusion, podocin has been demonstrated to play an important role to keep the normal glomerular permoselectivity and to be a therapeutical target molecule to be examined.

我们成功克隆了芬兰型先天性肾病综合征基因产物肾素的大鼠同源物，并发现尿蛋白诱导单克隆抗大鼠裂隙膜抗体5-1-6可识别大鼠肾素的细胞外位点。单次注射5-1-6所致的5-1-6肾病，以及肾病综合征的代表性大鼠模型PAN肾病，在蛋白尿开始前的早期就已经出现了nephrin表达的下降，提示nephrin表达的下降不是蛋白尿的结果，而是引起蛋白尿的原因，nephrin异常不仅与先天性肾脏病变密切相关，而且与获得性肾脏病变密切相关，尤其是与蛋白尿的诱导密切相关。我们还成功地克隆了最近报道的podocin，这是一种与家族性FSGS有关的基因产物。在5-1-6肾病和PAN肾病中，免疫荧光阳性染色模式从伪线状变为颗粒状，与肾素的情况一样。在5-1-6肾病中，podocin与nephrin共定位，但在PAN肾病中没有。在5-1-6肾病中，podocin在mRNA水平上表达降低。综上所述，podocin在保持肾小球过氧选择性方面发挥着重要作用，是一种有待研究的治疗靶分子。