Re-evaluation of pathological changes in glomerular diseases

• Applicant: Professor Dr. Wilhelm Kriz
• Subject Area: Pathology ; Nephrology
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 426321712

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.

• DFG Programme: Research Grants