Abstract: TH-PO071

Proteasomal or Lysosomal Degradation System Failures Have Different Consequences on Renal Cell Protein Homeostasis

Session Information

Category: Glomerular

  • 1002 Glomerular: Basic/Experimental Pathology

Authors

  • Sachs, Wiebke, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Di Lorenzo, Giorgia, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Sachs, Marlies, UKE , Hamburg, Germany
  • Pohl, Sandra, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Meyer-Schwesinger, Catherine, University of Hamburg, Hamburg, Germany
Background

Protein degradation plays an important role in protein quality control and therefore in cell homeostasis. Two different degradation systems are responsible for clearance of disused or defective proteins, the ubiquitin-proteasome system (UPS) and the autophagy-lysosome system (ALS), which are interconnected and influence each other. The aim of the project is to understand the significance of the proteasomal and lysosomal degradation systems for proteostasis of renal cells such as podocytes.

Methods

In order to dissect the significance of the UPS and ALS for renal cells, Balb/C mice were treated with epoxomicin (proteasomal inhibitor) and leupeptin (lysosomal inhibitor) respectively over 4 days. Furthermore, mice with general lysosomal dysfunction due to defective targeting of all newly synthesized lysosomal enzymes (Mucolipidosis type II, MLII) were analyzed. The effects of altered proteasomal and lysosomal functions were investigated clinically, morphologically and biochemically.

Results

Epoxomicin treatment resulted in a successful proteasomal inhibition. Mice developed proteinuria with abnormal glomerular protein accumulations in the subepithelial space and in podocytes. The tubulointerstitium was morphologically inconspicuous. Leupeptin treatment successfully reduced lysosomal function. Mice did not develop proteinuria. Morphological analyses were significant for abnormal accumulations in tubular cells and the mesangium of glomeruli. MLII mice showed severe lysosomal dysfunction in combination with proteasomal dysfunction in glomeruli and tubulointerstitial cells. Clinically, MLII mice showed slight proteinuria. Morphologically, MLII mice exhibited accumulations of enlarged lysosomes in interstitial cells, in the mesangium of glomeruli and in podocytes, with abnormal protein accumulations in podocytes.

Conclusion

Based on our results we conclude that the UPS and ALS interplay in renal cells and are compensatory upregulated when the other is inhibited. Failure of the proteasomal degradation system has a greater impact on renal cell proteostasis and renal function that cannot be compensated by the lysosomal degradation system.