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Abstract: FR-PO1046

Immunoproteasome-Deficiency Attenuates Antibody-Mediated Podocyte Injury

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Sachs, Wiebke, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Sachs, Marlies, UKE, Hamburg, Germany
  • Meyer-Schwesinger, Catherine, University of Hamburg, Hamburg, Germany

Group or Team Name

  • AG Meyer-Schwesinger
Background

Membranous nephropathy (MN) is an autoimmune disease characterized by subepithelial immune complex deposition and podocyte injury. Persistent podocyte injury during MN is associated with the upregulation of the ubiquitin-proteasome system (UPS), wherein the immunoproteasome is responsible for enhanced protein degradation and for generating peptides for MHC class I presentation. Here we address the impact of immunoproteasome-deficiency on the development of antibody-mediated podocyte injury.

Methods

Anti-podocyte nephritis (APN), a model for MN, was induced in global-β5i and podocyte-specific β5i deficient mice as well as littermate controls. As clinical parameters urine albumin/creatinine and BUN were measured. Morphological analysis of the kidney was obtained via PAS staining. Proteasomal function and activity of isolated glomeruli were analyzed via Western Blot and proteasomal activity assays.

Results

The development of proteinuria during APN was attenuated in global- and podocyte-specific β5i deficient mice compared to wildtype littermates. Western blot analysis revealed the upregulation of the standard proteasome in β5i deficient mice during APN. This was also shown in the upregulation of the chymotrypsin-like activity (the major proteasomal activity) in the β5i deficient mice.

Conclusion

Immunoproteasome-deficiency protects against antibody-mediated podocyte injury in mice. This can be explained by the upregulation of the standard proteasome, which leads to a different quantity and quality of peptide generation.

Funding

  • Government Support - Non-U.S.