Abstract: FR-PO732
Loss of Vasorin (VASN) Promotes Podocyte Cell-Cycle Reentry and Dedifferentiation: A Novel FSGS Mechanism and Disease Modifier?
Session Information
- Glomerular Diseases: Mechanisms and Podocyte Biology
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Tharaux, Pierre-Louis, Paris Centre de Recherche Cardiovasculaire, Paris, Île-de-France, France
- Dang, Julien, Paris Centre de Recherche Cardiovasculaire, Paris, Île-de-France, France
- Mahtal, Nassim, Paris Centre de Recherche Cardiovasculaire, Paris, Île-de-France, France
- Chaba, Anis, Paris Centre de Recherche Cardiovasculaire, Paris, Île-de-France, France
- Karras, Alexandre, Paris Centre de Recherche Cardiovasculaire, Paris, Île-de-France, France
- Endlich, Nicole, Universitatsmedizin Greifswald, Greifswald, Germany
- Lenoir, Olivia, Paris Centre de Recherche Cardiovasculaire, Paris, Île-de-France, France
Background
Podocyte loss of quiescence contributes to focal segmental glomerulosclerosis (FSGS) and crescentic glomerulonephritis (CGN).
Here, we characterized the role of Vasorin (VASN), a protein highly expressed in mature podocytes.
Methods
We combined laser capture microdissection with RNA sequencing of human glomeruli, RNAscope-based in situ hybridization, immunostaining, and mouse models with selective targeting of the Vasn gene in podocytes and cultures of human podocytes.
Results
VASN mRNA is strongly expressed in healthy human and mouse glomeruli with a podocyte-specific pattern. Both global and podocyte-specific, constitutive or inducible gene deletion of Vasn in mice induced nephrotic syndrome and kidney failure after day 14, with podocyte dedifferentiation and loss and severe FSGS, indicating a fundamental role of VASN in podocyte homeostasis. Furthermore, we measured markedly decreased VASN expression in podocytes of patients with FSGS and ANCA-associated CGN but not with Minimal Change Disease and Membranous Nephropathy. We then wondered whether VASN abundance could be a disease modifier. Mice with podocyte-specific heterozygous deletion of Vasn displayed accentuated podocyte loss, albuminuria, and kidney failure when challenged with diabetes or CGN experimental models.
Human podocytes transduced with lentiviral VASN-targeting shRNA (shVASN) displayed increased focal adhesion dynamics, enhanced migratory capacity, and epithelial-mesenchymal transition (EMT). shVASN podocytes had a higher proliferative capacity and increased cell-cycle reentry. Accordingly, shVASN podocytes and isolated mouse VASN-deficient glomeruli displayed up-regulation of genes involved in cell metabolism, adhesion, and EMT and down-regulation of genes involved in the S to G2/M phase transition. We confirmed that VASN deficiency increased podocyte proliferation in vivo and urinary shedding.
Conclusion
These findings indicatte the role of VASN as an essential master protein that maintains podocyte quiescence and homeostasis during health and kidney diseases. VASN controls mechanisms driving podocyte cell-cycle reentry and detachment, promoting extracapillary diseases.
VASN expression level may also discriminate various glomerular diseases trajectories.