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

肾脏疾病的分子基础 - 肾小球中新型小硫酸乙酰肝素蛋白多糖的功能

• 批准号: 5250688
• 负责人: Professor Dr. Jürgen Floege
• 金额: --
• 依托单位: Klinik für Nieren- und Hochdruckkrankheiten, Rheumatologische und Immunologische Erkrankungen (Medizinische Klinik II)
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2000
• 资助国家: 德国
• 起止时间: 1999-12-31 至 2002-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/5250688?language=en
• 关键词: Molekulare; Mechanismen; der; chronischen; Glomerulonephritis

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.

目前，对慢性肾小球肾炎（GN）的病因和分子机制仅部分了解。炎症过程的一个主要靶点是肾小球基底膜（GBM），而GBM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。基膜的主要分子结构在过去的二十年中已经被阐明，并表明硫酸肝素蛋白多糖（HS-PG）负责GBM的过选择性过滤过程，去除HS-PG会导致蛋白尿。虽然先前perlecan是唯一已知的基底膜HS-PG，但现在有证据表明（至少有两种）其他基底膜HS-PG确实存在：Agrin，最初是作为神经肌肉连接处的重要组成部分发现的，以及我们从人主动脉和肾脏中分离出的一种新型小HS-PG。该HS-PG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和22 kDa，通过免疫组化定位于基底膜。氨基酸序列分析表明，这种小的HS-PG与perlecan和agrin明显不同。因此，一个重要的问题是，这三种基膜HS-PG是多余的，还是它们在基膜内具有特定的功能。本项目的目的是分析新型小基底膜HS-PG在肾脏病GBM中的作用，特别是其在GBM选择性通透性中预防蛋白尿的作用。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有重要贡献，并可能促进这些疾病的新治疗方法的发展。