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

纤毛素-1和埃米林是细胞外基质(ECM)的微原纤维相关蛋白。它们有助于组织弹性，也可能起到将基底膜固定在间质结构上的作用。在存在高静水压的肾小球中，肾小球基底膜(GBM)下的系膜表达纤维蛋白-1、艾米林和VI型胶原。我们推测：(1)纤维蛋白-1、埃米林和VI型胶原对肾小球系膜上的基底膜锚定，从而对肾小球毛细血管的完整性起重要作用；(2)这些蛋白在对毛细血管的非生理性机械应力状态下表达上调，例如由于肾小球肥大和/或高血压。我们建议分别在纤维蛋白-1、艾米林或VI型胶原表达缺陷或表达减少的基因突变小鼠中测试这些假设。他们的肾脏表型将被分析，特别是关于肾小球异常(例如基底膜脱离，微动脉瘤的形成)。此外，将叠加导致肾小球肥大和/或高血压的实验性疾病(五分之五的肾切除术、糖尿病、动脉高血压)。对基因突变小鼠和野生型小鼠的肾脏损伤进行比较，可以得出结论，在正常和病理条件下，所研究的微原纤维相关蛋白在肾小球结构和功能的动态平衡中具有相关性。

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.