Abstract: TH-PO404
Piezo1 Promotes Podocyte Survival and Regeneration by Regulating F-actin Remodeling
Session Information
- Development, Organoids, Injury, and Regeneration
October 24, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Development, Stem Cells, and Regenerative Medicine
- 600 Development, Stem Cells, and Regenerative Medicine
Authors
- Melica, Maria Elena, Universita degli Studi di Firenze, Firenze, Florence, Italy
- Antonelli, Giulia, Universita degli Studi di Firenze, Firenze, Florence, Italy
- Carangelo, Giulia, Universita degli Studi di Firenze, Firenze, Florence, Italy
- Angelotti, Maria Lucia, Universita degli Studi di Firenze, Firenze, Florence, Italy
- Lazzeri, Elena, Universita degli Studi di Firenze, Firenze, Florence, Italy
- Conte, Carolina, Universita degli Studi di Firenze, Firenze, Florence, Italy
- Peired, Anna Julie, Universita degli Studi di Firenze, Firenze, Florence, Italy
- De Chiara, Letizia, Universita degli Studi di Firenze, Firenze, Florence, Italy
- Mazzinghi, Benedetta, Meyer - Azienda Ospedaliera Universitaria, Firenze, Florence, Italy
- Romagnani, Paola, Universita degli Studi di Firenze, Firenze, Florence, Italy
- Lasagni, Laura, Universita degli Studi di Firenze, Firenze, Florence, Italy
Background
Podocytes and podocyte progenitors are interdependent components of the kidney's glomerular structure, with podocytes forming the glomerular filtration barrier and progenitors being key players in podocyte regeneration during pathophysiological processes. Both cell types are subjected to constant mechanical forces, whose alterations can initiate podocytopathy and worsen glomerular injury. Despite this, the specific mechanosensors and mechanotransduction pathways involved in their response to mechanical cues remain partially explored.
Methods
We used transcriptomics, immunofluorescence, and silencing experiments on human primary progenitor cell cultures to demonstrate the expression and function of Piezo1 channels. We generated podocyte- and podocyte progenitor-specific Piezo1 knockout mice and evaluated the effects of Piezo1 loss in the context of Adriamycin nephropathy (ADN) and aging.
Results
Silencing of Piezo1 in progenitors triggered F-actin remodelling, induced cell shape modification and nuclear envelope defects with accumulation of DNA damage that lead to mitotic catastrophe in differentiated podocytes. Podocyte progenitor-specific knockout of Piezo1 in mouse resulted in severe albuminuria following ADN. Podocyte-specific knockout of Piezo1 not only induced higher susceptibility to podocyte injury in ADN but also led to accumulation of DNA damage and albuminuria throughout aging.
Conclusion
These results underline the central role of mechanical force perception and mechanotransduction in the pathogenesis of glomerular disease and identify Piezo1 as a potential target of mechanodrugs in disease conditions.
Funding
- Government Support – Non-U.S.