Abstract: TH-PO028

Podocyte-Specific Knockout of the Neonatal Fc Receptor (FcRn) Does Not Protect against Induction of Immune Complex Mediated Glomerular Disease

Session Information

Category: Glomerular

  • 1001 Glomerular: Basic/Experimental Immunology and Inflammation

Authors

  • Dylewski, James Francis, University of Colorado Hospital, Aurora, Colorado, United States
  • Dobrinskikh, Evgenia, University of Colorado, Denver, Aurora, Colorado, United States
  • Lewis, Linda, University of Colorado Denver, Aurora, Colorado, United States
  • Garcia, Gabriela E., University of Colorado Denver, Aurora, Colorado, United States
  • Blaine, Judith, University of Colorado Denver, Aurora, Colorado, United States
Background

Podocytes have been postulated to act as non-hematopoietic antigen presenting cells (APCs). In typical APCs the neonatal Fc receptor is required for antigen presentation and induction of an immune response. Global knockout of FcRn has been shown to protect against immune-mediated kidney disease. Podocytes express FcRn and the aim of this study was to determine whether knockout of FcRn in podocytes ameliorates immune complex mediated kidney disease.

Methods

MHC II and costimulatory marker expression in wild type (WT) and FcRn knockout (KO) podocytes was characterized at baseline and after stimulation with IFNg using flow cytometry. We compared antigen presentation in WT and FcRn KO podocytes using an in vitro antigen presentation assay. We created a podocyte-specific FcRn KO mouse and examined albuminuria, renal histology, intraglomerular neutrophil accumulation, and C3 deposition after induction of anti-glomerular basement membrane (anti-GBM) nephritis. Fluorescence lifetime imaging (FLIM) was used to examine metabolic changes in the glomeruli of KO and control mice after induction of nephritis.

Results

We found that treatment with IFNg upregulated MHC II expression in both WT and FcRn KO podocytes. At baseline, WT podocytes expressed significantly more CD80 than FcRn KO podocytes and there was no increase in CD80 expression in the KO after treatment with IFNg. Neither WT nor KO podocytes expressed CD86 at baseline or after treatment with IFNg. When treated with immune complexes in an in vitro antigen presentation assay, WT podocytes induced a very modest increase in T-cell IL-2 production whereas KO podocytes did not stimulate T cells at all.
There was no difference in BUN, albuminuria, intraglomerular neutrophil infiltration, C3 deposition, glomerulosclerosis score, or percent crescents in control versus podocyte-specific FcRn KO mice after induction of anti-GBM disease. FLIM demonstrated a decreased shift in glycolysis in KO mice compared to control after disease induction.

Conclusion

This study demonstrates that podocytes are inefficient antigen presenting cells and podocyte specific KO of FcRn does not prevent induction of anti-GBM disease.

Funding

  • NIDDK Support