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Atp6ap2 ablation in adult mice impairs viability through multiple organ deficiencies

ATP6AP2 codes for the (pro)renin receptor and is an essential component of vacuolar H+ ATPase. Activating (pro)renin for conversion of Angiotensinogen to Angiotensin makes ATP6AP2 attractive for drug intervention. Tissue-specific ATP6AP2 inactivation in mouse suggested a strong impact on various org...

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Autores principales: Wendling, Olivia, Champy, Marie-France, Jaubert, Solène, Pavlovic, Guillaume, Dubos, Aline, Lindner, Loic, Jacobs, Hugues, Mark, Manuel, Combe, Roy, Da Cruz, Isabelle Goncalves, Luche, Hervé, Mudgett, John S., Rosahl, Thomas, Sorg, Tania, Malissen, Marie, Reilly, Patrick T., Hérault, Yann
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5575319/
https://www.ncbi.nlm.nih.gov/pubmed/28851918
http://dx.doi.org/10.1038/s41598-017-08845-7
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author Wendling, Olivia
Champy, Marie-France
Jaubert, Solène
Pavlovic, Guillaume
Dubos, Aline
Lindner, Loic
Jacobs, Hugues
Mark, Manuel
Combe, Roy
Da Cruz, Isabelle Goncalves
Luche, Hervé
Mudgett, John S.
Rosahl, Thomas
Sorg, Tania
Malissen, Marie
Reilly, Patrick T.
Hérault, Yann
author_facet Wendling, Olivia
Champy, Marie-France
Jaubert, Solène
Pavlovic, Guillaume
Dubos, Aline
Lindner, Loic
Jacobs, Hugues
Mark, Manuel
Combe, Roy
Da Cruz, Isabelle Goncalves
Luche, Hervé
Mudgett, John S.
Rosahl, Thomas
Sorg, Tania
Malissen, Marie
Reilly, Patrick T.
Hérault, Yann
author_sort Wendling, Olivia
collection PubMed
description ATP6AP2 codes for the (pro)renin receptor and is an essential component of vacuolar H+ ATPase. Activating (pro)renin for conversion of Angiotensinogen to Angiotensin makes ATP6AP2 attractive for drug intervention. Tissue-specific ATP6AP2 inactivation in mouse suggested a strong impact on various organs. Consistent with this, we found that embryonic ablation of Atp6ap2 resulted in both male hemizygous lethality and female haploinsufficiency. Next, we examined the phenotype of an induced inactivation in the adult animal, most akin to detect potential effect of functional interference of ATP6AP2 through drug therapy. Induced ablation of Atp6ap2, even without equal efficiency in all tissues (aorta, brain and kidney), resulted in rapid lethality marked by weight loss, changes in nutritional as well as blood parameters, leukocyte depletion, and bone marrow hypoplasia. Upon Atp6ap2 ablation, the colon demonstrated a rapid disruption of crypt morphology, aberrant proliferation, cell-death activation, as well as generation of microadenomas. Consequently, disruption of ATP6AP2 is extremely poorly tolerated in the adult, and severely affects various organ systems demonstrating that ATP6AP2 is an essential gene implicated in basic cellular mechanisms and necessary for multiple organ function. Accordingly, any potential drug targeting of this gene product must be strictly assessed for safety.
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spelling pubmed-55753192017-09-01 Atp6ap2 ablation in adult mice impairs viability through multiple organ deficiencies Wendling, Olivia Champy, Marie-France Jaubert, Solène Pavlovic, Guillaume Dubos, Aline Lindner, Loic Jacobs, Hugues Mark, Manuel Combe, Roy Da Cruz, Isabelle Goncalves Luche, Hervé Mudgett, John S. Rosahl, Thomas Sorg, Tania Malissen, Marie Reilly, Patrick T. Hérault, Yann Sci Rep Article ATP6AP2 codes for the (pro)renin receptor and is an essential component of vacuolar H+ ATPase. Activating (pro)renin for conversion of Angiotensinogen to Angiotensin makes ATP6AP2 attractive for drug intervention. Tissue-specific ATP6AP2 inactivation in mouse suggested a strong impact on various organs. Consistent with this, we found that embryonic ablation of Atp6ap2 resulted in both male hemizygous lethality and female haploinsufficiency. Next, we examined the phenotype of an induced inactivation in the adult animal, most akin to detect potential effect of functional interference of ATP6AP2 through drug therapy. Induced ablation of Atp6ap2, even without equal efficiency in all tissues (aorta, brain and kidney), resulted in rapid lethality marked by weight loss, changes in nutritional as well as blood parameters, leukocyte depletion, and bone marrow hypoplasia. Upon Atp6ap2 ablation, the colon demonstrated a rapid disruption of crypt morphology, aberrant proliferation, cell-death activation, as well as generation of microadenomas. Consequently, disruption of ATP6AP2 is extremely poorly tolerated in the adult, and severely affects various organ systems demonstrating that ATP6AP2 is an essential gene implicated in basic cellular mechanisms and necessary for multiple organ function. Accordingly, any potential drug targeting of this gene product must be strictly assessed for safety. Nature Publishing Group UK 2017-08-29 /pmc/articles/PMC5575319/ /pubmed/28851918 http://dx.doi.org/10.1038/s41598-017-08845-7 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Wendling, Olivia
Champy, Marie-France
Jaubert, Solène
Pavlovic, Guillaume
Dubos, Aline
Lindner, Loic
Jacobs, Hugues
Mark, Manuel
Combe, Roy
Da Cruz, Isabelle Goncalves
Luche, Hervé
Mudgett, John S.
Rosahl, Thomas
Sorg, Tania
Malissen, Marie
Reilly, Patrick T.
Hérault, Yann
Atp6ap2 ablation in adult mice impairs viability through multiple organ deficiencies
title Atp6ap2 ablation in adult mice impairs viability through multiple organ deficiencies
title_full Atp6ap2 ablation in adult mice impairs viability through multiple organ deficiencies
title_fullStr Atp6ap2 ablation in adult mice impairs viability through multiple organ deficiencies
title_full_unstemmed Atp6ap2 ablation in adult mice impairs viability through multiple organ deficiencies
title_short Atp6ap2 ablation in adult mice impairs viability through multiple organ deficiencies
title_sort atp6ap2 ablation in adult mice impairs viability through multiple organ deficiencies
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5575319/
https://www.ncbi.nlm.nih.gov/pubmed/28851918
http://dx.doi.org/10.1038/s41598-017-08845-7
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