Re-evaluation of pathological changes in glomerular diseases

新的见解从根本上改变了我们对足细胞生物学的看法。这些措施是：首先，大部分足细胞由于作为活细胞从GBM脱离而损失，这意味着流变力最终导致它们的损失。第二，除了灌注压（张应力）对肾小球的挑战之外，滤液流的剪切应力的挑战作为肾小球病理变化的原因起着至关重要的作用。第三，磨损的GBM的降解发生在系膜中。肾小球系膜基质的积累，如在糖尿病肾病中所见，主要来自于未降解的GBM物质的沉积;这可能也适用于其他肾小球疾病，根据这些方面的病理变化的解释导致了令人惊讶的新观点关于肾小球疾病的发病机制。本项目旨在研究这些问题在肾小球疾病模型和活检中的相关性。在（A）组中，我们想研究肾小球高血压引起的损伤是否主要来自系膜衰竭。足细胞的变化，最终导致其脱离和进步FSGS似乎是依赖于先前的系膜衰竭。在组（B）中，我们想研究未降解的GBM材料在系膜中的沉积，如我们在糖尿病肾病活检中所示（即不能降解磨损的GBM材料），是否也是糖尿病肾病模型以及其他人类肾小球疾病中系膜基质扩张的基础。这将导致一个完全不同的系膜基质扩张的发病相关性。

New insights have fundamentally changed our ideas concerning the biology of podocytes. These are: First, podocytes for the major part are lost by detachment from the GBM as viable cells, meaning that the rheological forces were finally responsible for their loss. Second, in addition to the challenge of the glomerulus by the perfusion pressure (tensile stress), the challenge by the shear stress of the filtrate flow plays a crucial role as a causer of glomerular pathological changes. Third, the degradation of worn-out GBM takes place in the mesangium. The accumulation of mesangial matrix, as seen in diabetic nephropathy, emerges predominantly from the deposition of un-degraded GBM-material; this may be valid also for other glomerular diseases.The interpretation of the pathological changes under these aspects leads to surprisingly new views concerning the pathogenesis of glomerular diseases. This project aims to study the relevance of these questions in models and biopsies of glomerular diseases.In group (A) we want to study whether the injuries that are derived from glomerular hypertension arise primarily from mesangial failures. The podocyte changes that eventually lead to their detachment and advancement to FSGS seem to be dependent on the preceding mesangial failures. This hypothesis might be relevant for cases of secondary FSGS in general.In group (B) we want to investigate whether the deposition of un-degraded GBM-material in the mesangium, as shown by us in biopsies of diabetic nephropathy (i.e. the inability to degrade worn-out GBM-material), may underlie mesangial matrix expansion also in models of diabetic nephropathy as well as in other human glomerular diseases. This would lead to a totally different pathogenetic relevance of mesangial matrix expansion.