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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
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.
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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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