Re-evaluation of pathological changes in glomerular diseases

肾小球疾病病理变化的重新评估

• 批准号: 426321712
• 负责人: Professor Dr. Wilhelm Kriz
• 金额: --
• 依托单位: Institute for Innate Immunoscience (MI3)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/426321712?language=en
• 关键词: Re; evaluation; pathological; changes; glomerular

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.

新的见解从根本上改变了我们对足细胞生物学的看法。它们是：首先，足细胞的主要部分是由于脱离GBM作为活细胞而丢失的，这意味着流变力最终导致了它们的丢失。其次，除了灌注压力（张应力）对肾小球的挑战外，滤液流动剪切应力的挑战作为肾小球病理改变的原因起着至关重要的作用。第三，磨损的GBM降解发生在系膜。肾小球系膜基质的积累，如糖尿病肾病中所见，主要来自未降解的gbm物质的沉积；这也适用于其他肾小球疾病。对这些方面病理变化的解释，使我们对肾小球疾病的发病机制有了令人惊讶的新认识。本项目旨在研究这些问题在肾小球疾病的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是由肾小球系膜衰竭引起的。足细胞的改变最终导致其脱离并进展为FSGS，似乎依赖于先前的系膜失败。这一假设可能与继发性FSGS病例有关。在(B)组中，我们想研究是否如我们在糖尿病肾病活检中所显示的，未降解的gbm物质在系膜中的沉积（即不能降解磨损的gbm物质）可能也是糖尿病肾病模型和其他人类肾小球疾病中系膜基质扩张的基础。这将导致系膜基质扩张的完全不同的病理相关性。