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Abstract: FR-PO720

Proteasomal Processivity Influences the Endocytic Activity of Glomerular Cells

Session Information

Category: Glomerular Diseases

  • 1304 Glomerular Diseases: Podocyte Biology


  • Sachs, Wiebke, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Heintz, Lukas, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Zielinski, Stephanie, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Rinschen, Markus M., Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Kretz, Oliver, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Loreth, Desiree, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Meyer-Schwesinger, Catherine, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany

Glomerular injury is accompanied by intra- and extracellular protein accumulations. Degradation of proteins assures protein quality and prevents the cellular accumulation of unwanted proteins. Whether proteostatic mechanisms of glomerular cells assures the integrity and patency of the glomerular filter by preventing pathological protein accumulations is unknown. The two main intracellular proteolytic systems (ubiquitin-proteasome system (UPS), and autophagosomal-lysosome pathway (ALP)), are both ubiquitin dependent and thereby interconnected. We dissected the physiological cell-type significance of the UPS and ALP for glomerular protein accumulations, and filtration barrier function.


Human and murine glomerular cell-type specific UPS and ALP expression and activity was assessed by proteomic, histologic, and biochemical approaches. The impact of proteasomal or lysosomal inhibition on glomerular cell proteostasis, filtration barrier function, and endocytosis was analyzed clinically, morphologically, and biochemically in BALB/c mice and mechanistically in primary culture podocytes.


Podocytes and endothelial cells express distinct active proteasome subtypes, while mesangial cells show a high lysosomal abundance. Treatment with a pan-proteasomal but not with a lysosomal inhibitor result in albuminuria and glomerular tuft enlargement with ultrastructural podocyte and endothelial cell alterations. Tuft enlargement in proteasome-inhibited mice is the result of intra- and extracellular glomerular protein accumulations, especially at the filtration barrier. Mechanistically, a downregulation of endocytic receptors in podocytes and an impaired endocytic uptake of extracellular proteins contributes to the glomerular protein accumulation upon proteasomal inhibition.


Proteasomal impairment alters glomerular filtration barrier function and protein clearance in a cell-type specific manner, partly due to a differential regulation of endocytic receptors.


  • Government Support – Non-U.S.