Abstract: FR-PO833
HSP27 Promotes Activation of Parietal Epithelial Cells and Crescent Formation in Crescentic Glomerulonephritis
Session Information
- Glomerular Diseases: Inflammation and Immunology
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
- Melis, Lisa, Inserm U1155, Paris, France
- Sakhi, Hamza, Institut Mondor de Recherche Biomedicale, Creteil, France
- Gallazzini, Morgan, Institut Necker-Enfants Malades, Paris, Île-de-France, France
- Pate, Léonie, Inserm U1155, Paris, France
- Garrido, Carmen, INSERM U1231, Dijon, France
- Audard, Vincent, Hopital Henri Mondor, Creteil, Île-de-France, France
- El Karoui, Khalil, Inserm U1155, Paris, France
Background
Crescentic glomerulonephritis (CrGN) is the most severe form of kidney disease. CrGN is characterized by a pathological accumulation of parietal epithelial cells (PEC) forming the cellular “crescent” in the urinary space leading to end stage renal disease in 30-50% of cases. While current treatments consist of immunosuppressive therapies, none of them directly targets molecular pathways associated with crescent formation and PEC activation. Heat Shock Protein 27 (HSP27) is a stress-induced chaperone protein largely known for its anti-apoptotic and pro-proliferative effect in cancer. Here, we aim to investigate whether HSP27 is involved in PEC activation and crescent formation.
Methods
To explore the role of HSP27, we used a nephrotoxic serum (NTS)–induced crescentic glomerulonephritis preclinical model and biopsies from patients diagnosed with CrGN. In vitro, we used primary cell cultures of PEC, either with or without HSP27 knockdown, to examine migration, proliferation, and the expression of activation markers (CD44, EGF receptor activation).
Results
HSP27 is largely overexpressed in PEC within glomerular crescents in both patients with CrGN and in kidneys from NTS-treated mice. Targeting of HSP27 with the antisense oligonucleotide (OGX-427) results in reduced development of crescents in the NTS model. In vitro, pharmacologic or genetic silencing of HSP27 in PEC induces a reduction in cellular migration and activation (measured by CD44 expression). These data suggest that HSP27 could promote crescents formation by promoting PEC activation and proliferation. To better understand, we explored the EGFr pathway known to be involved in glomerular epithelial cells activation. Silencing of HSP27 leads to a reduction in the activation of the EGF receptor, explaining at least part of the impact in PEC activation.
Conclusion
Taken together, our data highlight a role for HSP27 in the development of crescent lesions and pave the way for innovative therapeutic approaches for CrGN patients.
Funding
- Government Support – Non-U.S.