Kidney Week

Abstract: TH-PO767

MHC Class I Molecules and Dendrin Are Upregulated in Primary FSGS Podocytes

Session Information

• Glomerular Diseases: Podocyte Biology - I
  November 02, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1403 Podocyte Biology

Authors

• Deleersnijder, Dries, Katholieke Universiteit Leuven, Leuven, Vlaams-Brabant, Belgium

Dries Deleersnijder,

• Bihary, Dora, Vlaams Instituut voor Biotechnologie KU Leuven Center for Cancer Biology, Leuven, Vlaams-Brabant, Belgium

Dora Bihary,

• Sprangers, Ben, Ziekenhuis Oost-Limburg, Genk, Limburg, Belgium

Ben Sprangers,

• Meijers, Björn Ki, Katholieke Universiteit Leuven, Leuven, Vlaams-Brabant, Belgium

Björn Ki Meijers,

• Lambrechts, Diether, Vlaams Instituut voor Biotechnologie KU Leuven Center for Cancer Biology, Leuven, Vlaams-Brabant, Belgium

Diether Lambrechts,

• Van Craenenbroeck, Amaryllis H., Katholieke Universiteit Leuven, Leuven, Vlaams-Brabant, Belgium

Amaryllis H. Van Craenenbroeck,

Background

The pathophysiology of primary focal segmental glomerulosclerosis (FSGS) is incompletely understood, and differentiation between FSGS subtypes remains challenging. We used single-cell transcriptomics to identify new pathways that are specifically deranged in primary FSGS podocytes.

Methods

We performed single-nucleus RNA-sequencing (10x Genomics Chromium) on cryopreserved kidney biopsy cores from patients with primary FSGS (n=9, all nephrotic), maladaptive FSGS (n=9, none nephrotic), proteinuric controls (PLA2R-positive membranous nephropathy, n=3), and healthy controls (pre-perfusion biopsies, n=4).

Results

We identified 194,594 nuclei, of which 3,660 were podocytes expressing canonical marker genes (Figure 1A). Differential gene expression analysis between primary FSGS podocytes (n=1,635 nuclei) and all other podocytes (n=2,025 nuclei) showed significant upregulation of genes encoding major histocompatibility complex (MHC) class I proteins (HLA-A, HLA-B, HLA-E, B2M) and dendrin (DDN) (Figure 1B-C). Overexpression of MHC class I molecules has previously been observed in autoimmune diseases such as diabetes mellitus¹. We hypothesize that presentation of self-antigens in primary FSGS podocytes via MHC class I proteins may either be an initiating event, triggering production of a pathogenic permeability factor, or alternatively an adaptive response to earlier podocyte injury. Dendrin, which interacts with slit diaphragm proteins, translocates to the nucleus in injured podocytes, triggering apoptosis in mouse models of FSGS², thereby making it a promising new target in human primary FSGS.

Conclusion

MHC class I molecules and dendrin represent two novel differentially expressed pathways that could aid in further distinguishing different FSGS subtypes.

References:
1: Russell, et al. Diabetes. 2019.
2: Empitu, et al. J Am Soc Nephrol. 2023.