Abstract: PO1686
Drosophila Filamin Exhibits a Mechanoprotective Role During Nephrocyte Injury via Hypertrophy
Session Information
- Podocyte Pathobiology: Basic Science Studies and Animal Models
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1204 Podocyte Biology
Authors
- Koehler, Sybille, Biomedical Sciences, University of Edinburgh, Edinburgh, United Kingdom
- Denholm, Barry, Biomedical Sciences, University of Edinburgh, Edinburgh, United Kingdom
Background
Podocytes are constantly exposed to biomechanical forces such as shear stress and hydrostatic pressure. These forces increase during disease like diabetes and hypertension, resulting in adaptive mechanisms such as podocyte hypertrophy. But how do podocytes sense changes in biomechanical forces and how does the molecular response look like?
Methods
To investigate this, we utilized Drosophila nephrocytes and studied the functional role of the mechanosensor Cheerio (dFilamin). FilaminB is upregulated in podocyte injury models and upon increased biomechanical stress, therefore serving as an ideal candidate for mediating mechano-protection in response to injury.
Results
Expression of an over-active mechanosensor region variant of Cheerio resulted in a significant hypertrophy phenotype, while morphology and filtration function were only mildly affected. Interestingly, the expression of over-active Cheerio caused a rescue of filtration function after depletion of the nephrocyte diaphragm proteins Duf (dNEPH) and Sns (dNephrin). Additional analysis with human FilaminB confirmed this mechano-protective role and the involvement of the mechanosensor region in the hypertrophy phenotype. To delineate the mechano-protective pathway acting downstream to Cheerio we studied the candidates: TOR, WNT and YAP. Activation of these pathways result in nephrocyte hypertrophy. Interestingly, TOR repression reversed the hypertrophy in over-active Cheerio expressing cells, suggesting TOR to be a novel downstream target of Cheerio and to be responsible for the hypertrophy phenotype.
Conclusion
Although Cheerio and FilaminB mediate a mechano-protective role in the face of injury, their excessive expression resulted in a severe morphological and functional phenotype, emphasizing the need of a tight control of expression levels.