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A YAP/TAZ–ARHGAP29–RhoA Signaling Axis Regulates Podocyte Protrusions and Integrin Adhesions
Glomerular disease due to podocyte malfunction is a major factor in the pathogenesis of chronic kidney disease. Identification of podocyte-specific signaling pathways is therefore a prerequisite to characterizing relevant disease pathways and developing novel treatment approaches. Here, we employed...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10340513/ https://www.ncbi.nlm.nih.gov/pubmed/37443829 http://dx.doi.org/10.3390/cells12131795 |
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author | Rogg, Manuel Maier, Jasmin I. Helmstädter, Martin Sammarco, Alena Kliewe, Felix Kretz, Oliver Weißer, Lisa Van Wymersch, Clara Findeisen, Karla Koessinger, Anna L. Tsoy, Olga Baumbach, Jan Grabbert, Markus Werner, Martin Huber, Tobias B. Endlich, Nicole Schilling, Oliver Schell, Christoph |
author_facet | Rogg, Manuel Maier, Jasmin I. Helmstädter, Martin Sammarco, Alena Kliewe, Felix Kretz, Oliver Weißer, Lisa Van Wymersch, Clara Findeisen, Karla Koessinger, Anna L. Tsoy, Olga Baumbach, Jan Grabbert, Markus Werner, Martin Huber, Tobias B. Endlich, Nicole Schilling, Oliver Schell, Christoph |
author_sort | Rogg, Manuel |
collection | PubMed |
description | Glomerular disease due to podocyte malfunction is a major factor in the pathogenesis of chronic kidney disease. Identification of podocyte-specific signaling pathways is therefore a prerequisite to characterizing relevant disease pathways and developing novel treatment approaches. Here, we employed loss of function studies for EPB41L5 (Yurt) as a central podocyte gene to generate a cell type-specific disease model. Loss of Yurt in fly nephrocytes caused protein uptake and slit diaphragm defects. Transcriptomic and proteomic analysis of human EPB41L5 knockout podocytes demonstrated impaired mechanotransduction via the YAP/TAZ signaling pathway. Further analysis of specific inhibition of the YAP/TAZ-TEAD transcription factor complex by TEADi led to the identification of ARGHAP29 as an EPB41L5 and YAP/TAZ-dependently expressed podocyte RhoGAP. Knockdown of ARHGAP29 caused increased RhoA activation, defective lamellipodia formation, and increased maturation of integrin adhesion complexes, explaining similar phenotypes caused by loss of EPB41L5 and TEADi expression in podocytes. Detection of increased levels of ARHGAP29 in early disease stages of human glomerular disease implies a novel negative feedback loop for mechanotransductive RhoA—YAP/TAZ signaling in podocyte physiology and disease. |
format | Online Article Text |
id | pubmed-10340513 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-103405132023-07-14 A YAP/TAZ–ARHGAP29–RhoA Signaling Axis Regulates Podocyte Protrusions and Integrin Adhesions Rogg, Manuel Maier, Jasmin I. Helmstädter, Martin Sammarco, Alena Kliewe, Felix Kretz, Oliver Weißer, Lisa Van Wymersch, Clara Findeisen, Karla Koessinger, Anna L. Tsoy, Olga Baumbach, Jan Grabbert, Markus Werner, Martin Huber, Tobias B. Endlich, Nicole Schilling, Oliver Schell, Christoph Cells Article Glomerular disease due to podocyte malfunction is a major factor in the pathogenesis of chronic kidney disease. Identification of podocyte-specific signaling pathways is therefore a prerequisite to characterizing relevant disease pathways and developing novel treatment approaches. Here, we employed loss of function studies for EPB41L5 (Yurt) as a central podocyte gene to generate a cell type-specific disease model. Loss of Yurt in fly nephrocytes caused protein uptake and slit diaphragm defects. Transcriptomic and proteomic analysis of human EPB41L5 knockout podocytes demonstrated impaired mechanotransduction via the YAP/TAZ signaling pathway. Further analysis of specific inhibition of the YAP/TAZ-TEAD transcription factor complex by TEADi led to the identification of ARGHAP29 as an EPB41L5 and YAP/TAZ-dependently expressed podocyte RhoGAP. Knockdown of ARHGAP29 caused increased RhoA activation, defective lamellipodia formation, and increased maturation of integrin adhesion complexes, explaining similar phenotypes caused by loss of EPB41L5 and TEADi expression in podocytes. Detection of increased levels of ARHGAP29 in early disease stages of human glomerular disease implies a novel negative feedback loop for mechanotransductive RhoA—YAP/TAZ signaling in podocyte physiology and disease. MDPI 2023-07-06 /pmc/articles/PMC10340513/ /pubmed/37443829 http://dx.doi.org/10.3390/cells12131795 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Rogg, Manuel Maier, Jasmin I. Helmstädter, Martin Sammarco, Alena Kliewe, Felix Kretz, Oliver Weißer, Lisa Van Wymersch, Clara Findeisen, Karla Koessinger, Anna L. Tsoy, Olga Baumbach, Jan Grabbert, Markus Werner, Martin Huber, Tobias B. Endlich, Nicole Schilling, Oliver Schell, Christoph A YAP/TAZ–ARHGAP29–RhoA Signaling Axis Regulates Podocyte Protrusions and Integrin Adhesions |
title | A YAP/TAZ–ARHGAP29–RhoA Signaling Axis Regulates Podocyte Protrusions and Integrin Adhesions |
title_full | A YAP/TAZ–ARHGAP29–RhoA Signaling Axis Regulates Podocyte Protrusions and Integrin Adhesions |
title_fullStr | A YAP/TAZ–ARHGAP29–RhoA Signaling Axis Regulates Podocyte Protrusions and Integrin Adhesions |
title_full_unstemmed | A YAP/TAZ–ARHGAP29–RhoA Signaling Axis Regulates Podocyte Protrusions and Integrin Adhesions |
title_short | A YAP/TAZ–ARHGAP29–RhoA Signaling Axis Regulates Podocyte Protrusions and Integrin Adhesions |
title_sort | yap/taz–arhgap29–rhoa signaling axis regulates podocyte protrusions and integrin adhesions |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10340513/ https://www.ncbi.nlm.nih.gov/pubmed/37443829 http://dx.doi.org/10.3390/cells12131795 |
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