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

我们已经成功地克隆了nephrin的大鼠同源物，nephrin是负责芬兰型先天性肾病综合征的基因的产物，并得出结论，蛋白尿诱导单克隆抗大鼠狭缝膜抗体5-1-6识别大鼠nephrin的细胞外位点。在由5- 1-6单次注射诱导的5 - 1 -6肾病中，以及在肾病综合征的代表性大鼠模型PAN肾病中，nephrin的表达在蛋白尿开始之前的早期阶段就已经降低，这表明nephrin表达的降低不是蛋白尿的结果，而是蛋白尿的原因，nephrin异常不仅与先天性而且与获得性肾脏病变密切相关，特别是蛋白尿的诱导。我们还成功地克隆了最近报道的podocin，一种负责家族性FSGS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由假线性变为颗粒状，就像nephrin的情况一样。在5-1-6肾病中，podocin与nephrin共定位，但在PAN肾病中不存在。podocin在5-1-6肾病中的表达明显降低，提示podocin在维持正常肾小球通透性选择性中起重要作用，可作为治疗性靶分子。

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.