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 glomerular basement membrane)

• Applicant: Professor Dr. Jürgen Floege
• Subject Area: Dermatology
• Term: from 2000 to 2003
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 5250688

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.

• DFG Programme: Priority Programmes
• Subproject of: SPP 1086: Genetic and Molecular Analysis of Basement Membranes and Basement Membrane Anchorage
• Participating Persons: Professor Dr. Hans-Dieter Haubeck; Professor Dr. Bernhard Heintz; Dr. Georg Stöcker