Molekulare Mechanismen der chronischen Glomerulonephritis - Funktion eines neuen kleinen Heparansulfat-Proteoglycans in der glomerulären Basalmembran (Molecular basis of renal disease - function of a novel small heparan sulfate proteoglycan in the glomeru

目前，慢性肾小球肾炎(GN)的病因和分子机制尚不完全清楚。炎症过程的一个主要靶点是肾小球基底膜，基底膜的改变会导致蛋白尿，这是肾小球肾炎的主要症状。蛋白尿是决定肾功能不全进展的关键因素。在过去的二十年里，人们阐明了基底膜的主要分子结构，结果表明，硫酸乙酰肝素蛋白多糖(HS-PG)负责GBM的渗透选择性过滤过程，而HS-PG的去除将导致蛋白尿。虽然以前Perlecan是唯一已知的基底膜HS-PG，但现在有证据表明，确实存在(至少两个)其他基底膜HS-PG：最初发现作为神经肌肉连接的重要成分的AGRIN和我们从人的主动脉和肾脏分离的一种新的小HS-PG。免疫组织化学方法定位于基底膜上的HS-PG，分子量分别为80-200 kDa(主动脉)和30-160 kDa(肾脏)，核心蛋白大小分别为24 kDa和22 kDa。氨基酸序列分析表明，该小分子HS-PG与Perlecan和Agrin有明显的区别。因此，一个重要的问题将是这三个基底膜HS-PG是否是多余的，或者它们在基底膜内发挥特定的功能。本项目的目的是分析新型小基底膜HS-PG在肾脏疾病的基底膜中的作用，特别是它在防止蛋白尿的基底膜选择性通透性中的作用。阐明新的小分子HS-PG在肾小球基底膜中的功能和相互作用，以及它在不同的肾小球肾炎动物模型中的作用，可能对我们理解肾脏疾病的分子基础有重要贡献，并可能为开发治疗这些疾病的新方法奠定基础。

At present, the etiology and the molecular mechanisms of chronic glomerulonephritis (GN) are only partially understood. A major target of the inflammatory process is the glomerular basement membrane (GBM) and alteration of the GBM will lead to proteinuria, a leading symptome of GN. Proteinuria in turn is the key factor which determines the progression of renal insufficiency. The principal molecular structure of basement membranes has been elucidated during the past two decades and it was shown that heparan sulfate proteoglycans (HS-PG) are responsible for the permselective filtration process of the GBM and that removal of HS-PG will lead to proteinuria. Whereas previously perlecan was the only known basement membrane HS-PG, there is now evidence that (at least two) other basement membrane HS-PG do exist: Agrin, originally discovered as an important component of the neuromuscular junction and a novel small HS-PG that we have isolated from human aorta and kidney. This HS-PG with a molecular weight of 80 - 200 kDa (aorta) and 30 - 160 kDa (kidney) and a core protein size of 24 kDa or 22 kDa, respectively, was localized by immunohistochemistry to the basement membrane. Amino acid sequence analysis of tryptic peptides revealed that this small HS-PG is clearly distinct from perlecan and agrin. Therefore, an important question will be whether these three basement membrane HS-PG are redundant or thether they serve specific functions within the basement membrane. The aim of the project is to analyze the role of the novel small basement membrane HS-PG in the GBM in renal disease and especially its role in the selective permeability of the GBM that prevents proteinuria. Elucidation of the function and interactions of the novel small HS-PG in the GBM and its role in different animal models of glomerulonephritis may be an iportant contribution to our understanding of the molecular basis of renal disease and may allow the development of novel therapeutic approaches for these diseases.