Abstract: FR-PO774
Functional Role of the Mechanosensitive Channel Piezo for Nephrocyte Biology
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
- Alornyo, Karl King, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Hazelton-Cavill, Paris, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Schulz, Kristina, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Edenhofer, Ilka, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Lindenmeyer, Maja, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Lohr, Christian, Universitat Hamburg Fakultat fur Mathematik Informatik und Naturwissenschaften, Hamburg, Hamburg, Germany
- Huber, Tobias B., Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Denholm, Barry, Biomedical Sciences, University of Edinburgh, Edinburgh, United Kingdom
- Koehler, Sybille, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
Background
Due to their position on glomerular capillaries, podocytes are continuously counteracting biomechanical filtration forces. Most therapeutic interventions known to generally slow or prevent the progression of chronic kidney disease appear to lower the biomechanical forces on podocytes, highlighting the critical need to better understand podocyte mechano-signalling pathways.
Methods
Here we investigated the hypothesis that the mechanotransducer Piezo is involved in a mechanosensation pathway in Drosophila nephrocytes, the podocyte homologue in the fly.
Results
Our data show Piezo is expressed in nephrocytes where it localises to the nephrocyte diaphragm. Loss of function analysis in Piezo depleted nephrocytes revealed a morphological and functional phenotype. Further, we show that elevated Piezo expression levels resulted in Rho1 hyperactivity and accumulation of actin stress fibres, culminating in a severe nephrocyte phenotype, suggesting that pathway hyperactivity is detrimental as well. Interestingly, expression of Piezo, which lacks mechanosensitive channel activity, did not result in a severe nephrocyte phenotype and activation of Rho1, suggesting the observed changes in Piezo wildtype overexpressing cells are caused by the mechanosensitive channel activity. Further, pharmacological activation of Piezo with Yoda1 caused a significant increase of intracellular Ca++ upon exposure to mechanical force in nephrocytes, as well as filtration disturbances and Rho1 activation. Moreover, blocking Piezo activity using the tarantula toxin GsMTx4 reversed filtration disturbances, Rho1 hyperactivation as well as actin stress fibre accumulation in nephrocytes overexpressing Piezo.
Conclusion
Taken together, these data show that Piezo plays an important role in nephrocyte mechanotransduction and mediates downstream signalling such as Rho1 activation and actin stress fibre formation.