Servicenavigation

Project Details

Back

Projekt Print View

The Role of Protein Degradation Systems for Glomerular Protein Homeostasis

Subject Area Nephrology
Term from 2019 to 2024
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 429327206
 
Final Report Year 2024

Final Report Abstract

Three types of glomerular cells, which form a functional syncytium, achieve renal filtration. Of these, podocytes and endothelial cells are separated by the glomerular basement membrane and ultimately compose the three-layered glomerular filtration barrier (GFB), which is thought to impart both size-selective and charge-selective properties. Mesangial cells occupy the space in-between the GFB to provide structural support and to indirectly participate in filtration by reducing the glomerular surface area by contraction. Typical for glomerular injury is the deposition of proteins originating from the plasma in form of subepithelial, subendothelial and mesangial deposits. Under physiologic conditions glomerular deposition of protein is neglectable even though permeability of the GFB to plasma protein is only partial, suggesting that preventive mechanisms must exist. Impairment of these mechanisms could result in pathologic glomerular protein deposition, which in turn would affect glomerular function. The basis of glomerular protein homeostasis is unknown partly due to the complexity of protein degradation systems and due to the complexity of the glomerular syncytium. In this proposal we hypothesized, that protein uptake and intracellular degradation through the two major degradative systems, namely the ubiquitin-proteasomal system (UPS) and the autophagosomal lysosomal pathway (ALP) interplay in glomerular cells and contribute to maintain the integrity of the glomerular filter in a cell-specific manner. To dissect the unknown physiologic and pathophysiologic importance of the UPS and ALP for the intra- and extracellular protein homeostasis of glomerular cells we defined three aims which were be addressed with novel techniques of glomerular cell-specific analyses. (1) Define the differential cell-specific basal activity of the UPS and the ALP in glomerular cells. (2) Comparative analyses of the consequence of clinically used proteasome inhibitors on the protein homeostasis of glomerular cells. (3) Comparative analyses of the consequence of genetic cell-specific proteasomal and lysosomal impairment for the unchallenged glomerular syncytium and after IgG exposition. We established a novel method of bulk glomerular cell type isolation from mice that enables the investigation of proteostatic principles of the glomerulus. Our results demonstrate that glomerular cell type homeostasis physiologically underlies differing proteostatic principles. Mesangial cells depend on the lysosome system, podocytes and glomerular endothelial cells on the (immune)proteasome system. The proteasome system ensures filtration barrier clearance of for example IgG through orchestration of endocytosis. Further, the proteasome system closely interacts with the lysosomal system in glomerular cells, compensating for lysosomal impairment. We identified urinary podocyte-derived extracellular vesicles as suitable non-invasive biomaterial for the biochemical/functional assessment of podocyte proteostasis alterations in patients. We also identified a novel podocyte reaction of autoantibody removal from the subepithelial space, termed exopher genesis which is triggered by proteotoxic stress such as proteasome inhibition. In patients, the monitoring of urinary exophers enables the detection of MN-autoantibodies even in the presence of autoantibody negative serum titers. Our cumulative results provide the basis for our understanding of the mechanisms of glomerular protein deposition, for understanding conflicting data on adverse drug effects of proteasome inhibitors, and of the different glomerular phenotypes of mutations involving UPS and ALS proteins. Further development of these new investigatory approaches and validation in larger patient cohorts will allow future prognostic deductions of the extent of podocyte injury and proteostatic alterations in individual patients and guide personalized diagnostics and prognostic decision making.

Publications

 
 

Additional Information

© 2026 DFG Disclaimer / Copyright / Privacy Policy

Textvergrößerung und Kontrastanpassung