Role of the interaction of slit membrane, podocyte and glomerular basement membrane in pathogenesis of glomerular kidney diseases such as Alport's syndrome

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Mutations in the glomerular filtration barrier like collagen type IV (COL4A3/4/5, glomerular basement membrane) or podocin (Nphs2, slit diaphragm) lead to an early begin of proteinuria, kidney fibrosis and end-stage-renal disease. Heterozygous COL4A3/4-mutation-carriers develop a thin basement membrane nephropathy with only hematuria later in life. Recently, adolescents have been described developing early proteinuria and kidney failure with only heterozygous collagen type IV-mutations. In these patients additional podocin-polymorphism were found. In this project, a possible pathogenetic correlation is planned to be investigated with help of double-heterozygous COL4A3+/-//Nphs2+/R140Q-mice. We hypothesize that between the glomerular basement membrane (GBM) and slit diaphragm (SD) an interaction exists via the podocytes' receptors. This link is essential for homeostasis and stability of the filtration barrier. We want to focus on the influence of a modifier-gene, like podocin, on the COL4A3-mice who develop TBMN. Our first results show an early proteinuria as well as pathological podocyte foot process effacement in these mice. Specifically, we want to focus on the influence of hyperfiltration on kidney fibrosis development due to uninephrectomy in COL4A3+/-//Nphs2+/R140Q-mice. Furthermore, the effect of ACE-inhibitor therapy after uninephrectomy before and during proteinuria will be investigated. These questions shall be studied on clinical parameters like survival time till kidney failure as primary end point, development of proteinuria/albuminuria, as well as histological and ultrastructural analysis of the kidneys. Furthermore, description of the GBM-, SD-composition and their receptors will be studied, in vivo and in vitro by immunohistochemistry, real-time PCR and Western Blot. This will also be studied with our well-established ultrastructural immunogoldhistochemistry during different disease stages. Our first results of the GBM- and SD-findings demonstrate that the double-heterozygous mice give rise to important insights in basic mechanisms of the link between podocyte, its GBM and SD, as well as their homeostasis. Our project has a significant clinical reference for human diseases like Alport Syndrome and focal segmental glomerulosclerosis. The expected results could also offer a new basic understanding for treatment options of more frequent kidney diseases like diabetic nephropathy or glomerulonephritis.