Bedeutung der mikrofibrillären Proteine Fibrillin-1, Emilin und Kollagen VI in der Verankerung der Basalmembran normaler und erkrankter Glomeruli (Role of microfibrillar proteins fibrillin-1, emilin and collagen type VI in basement membrane anchorage of n

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Fibrillin-1 and emilin are microfibril-associated proteins of the extracelular matrix (ECM). They contribute to tissue elasticity and may also function to anchor basement membranes to interstitial structures. In renal glomeruli, where high hydrostatic capillary pressures exist, fibrillin-1, emilin as well as type VI collagen are expressed in the mesangium where it underlies the glomerular basement membrane (GBM). We postulate that: (1) fibrillin-1, emilin and type VI collagen are important for GBM anchorage to the mesangium and thus, for integrity of the glomerular capillary tuft; and (2) these proteins are upregulated in states of unphysiologic mechanical stress to the capillaries, e.g. due to glomerular hypertrophy and/or hypertension. We propose to test these hypotheses in gene-mutated mice with defects or reduced expression of fibrillin-1, emilin or type VI collagen, respectively. Their renal phenotype will be analyzed, particularly with respect to glomerular abnormalities (e.g. GBM detachment, formation of microaneurysms). In addition, experimental diseases causing glomerular hypertrophy and/or hypertension will be superimposed (5/6th nephrectomy, diabetes mellitus, arterial hypertension). Comparison of the induced renal damage in genemutated vs. wildtype mice will allow conclusions as to the relevance of the studied microfibril-associated proteins in the homeostasis of glomerular structure and function under normal and pathological conditions.