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）的病因和分子机制仅部分了解。炎症过程的主要靶点是肾小球基底膜（GBM），GBM的改变将导致蛋白尿，这是GN的主要症状。蛋白尿反过来又是决定肾功能不全进展的关键因素。在过去的二十年中已经阐明了基底膜的主要分子结构，并且显示硫酸乙酰肝素蛋白聚糖（HS-PG）负责GBM的选择性渗透过滤过程，并且HS-PG的去除将导致蛋白尿。尽管此前串珠素是唯一已知的基底膜HS-PG，但现在有证据表明（至少两种）其他基底膜HS-PG确实存在：聚集蛋白，最初被发现为神经肌肉接头的重要组分，以及我们从人主动脉和肾脏中分离出的新型小HS-PG。该HS-PG的分子量为80 - 200 kDa（主动脉）和30 - 160 kDa（肾脏），核心蛋白大小分别为24 kDa或22 kDa，通过免疫组织化学定位于基底膜。胰蛋白酶肽的氨基酸序列分析表明，这种小HS-PG是明确不同的串珠素和聚集蛋白。因此，一个重要的问题是这三种基底膜HS-PG是否是多余的，或者它们在基底膜内发挥特定的功能。该项目的目的是分析新型小基底膜HS-PG在肾脏疾病GBM中的作用，特别是其在GBM选择性渗透性中的作用，以防止蛋白尿。阐明新型小HS-PG在GBM中的功能和相互作用及其在不同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做出重要贡献，并可能为这些疾病开发新的治疗方法。

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.