Protective role of renal proximal tubular alpha-synuclein in the pathogenesis of kidney fibrosis

Kidney fibrosis is a highly deleterious process and a final manifestation of chronic kidney disease. Alpha-(α)-synuclein (SNCA) is an actin-binding neuronal protein with various functions within the brain; however, its role in other tissues is unknown. Here, we describe the expression of SNCA in ren...

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Autores: Bozic, Milica, Caus Enríquez, Maite, Rodrigues-Diez, Raul, Pedraza González, Neus, Ruiz-Ortega, Marta, Garí Marsol, Eloi, Gallel Vicente, María del Pilar, Panadés, Maria José, Martínez, Ana, Fernández i Giráldez, Elvira, Valdivielso Revilla, José Manuel
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2020
País:España
Institución:Universitat de Lleida (UdL)
Repositorio:Repositori Obert UdL
OAI Identifier:oai:repositori.udl.cat:10459.1/68493
Acceso en línea:https://doi.org/10.1038/s41467-020-15732-9
http://hdl.handle.net/10459.1/68493
Access Level:acceso abierto
Palabra clave:Ronyons -- Fibrosi
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spelling Protective role of renal proximal tubular alpha-synuclein in the pathogenesis of kidney fibrosisBozic, MilicaCaus Enríquez, MaiteRodrigues-Diez, RaulPedraza González, NeusRuiz-Ortega, MartaGarí Marsol, EloiGallel Vicente, María del PilarPanadés, Maria JoséMartínez, AnaFernández i Giráldez, ElviraValdivielso Revilla, José ManuelRonyons -- FibrosiKidney fibrosis is a highly deleterious process and a final manifestation of chronic kidney disease. Alpha-(α)-synuclein (SNCA) is an actin-binding neuronal protein with various functions within the brain; however, its role in other tissues is unknown. Here, we describe the expression of SNCA in renal epithelial cells and demonstrate its decrease in renal tubules of murine and human fibrotic kidneys, as well as its downregulation in renal proximal tubular epithelial cells (RPTECs) after TGF-β1 treatment. shRNA-mediated knockdown of SNCA in RPTECs results in de novo expression of vimentin and α-SMA, while SNCA overexpression represses TGF-β1-induced mesenchymal markers. Conditional gene silencing of SNCA in RPTECs leads to an exacerbated tubulointerstitial fibrosis (TIF) in two unrelated in vivo fibrotic models, which is associated with an increased activation of MAPK-p38 and PI3K-Akt pathways. Our study provides an evidence that disruption of SNCA signaling in RPTECs contributes to the pathogenesis of renal TIF by facilitating partial epithelial-to-mesenchymal transition and extracellular matrix accumulation.This work was supported by research grants PI15/00960 and PI17/00119 from the Instituto de Salud Carlos III (ISCII, Spanish Ministry of Economy and Competitiveness) and REDinREN (RD12/0021). The work on human kidney tissue samples was supported by the IRBLleida Biobank (B.0000682) and PLATAFORMA BIOBANCOS PT17/0015/0027. M.B. was supported by the REDinREN (RD12/0021/0026) and Department of Health, Government of Catalonia (PERIS 2016-2020, SLT002/16/00178). M.C. was supported by the studentship from the Catalan Government (AGAUR). R.R.R-D. was supported by a grant from the Comunidad Autonóma de Madrid (B2017/BMD-3751 NOVELREN-CM). We thank Dr. Bernard Schneider (Swiss Federal Institute of Technology Lausanne, Switzerland) for providing pSIN-pgk-human Synuclein WT-WPRE plasmid, Dr. Guadalupe Sabio (CNIC, Madrid, Spain) for providing HA-p38 PCNA plasmid, and Dr. Volker Haase (Vanderbilt University, TN, USA) for providing PEPCK-Cre+ transgenic mice. We thank Laura Santos-Sanchez (Universidad Autonoma Madrid) for helping with collagen evaluation and immunohistochemistry studies, and Alicia Garcia (IRBLleida) for valuable technical help in the laboratory.Nature Publishing Group2020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://doi.org/10.1038/s41467-020-15732-9http://hdl.handle.net/10459.1/68493reponame:Repositori Obert UdL instname:Universitat de Lleida (UdL)InglésReproducció del document publicat a https://doi.org/10.1038/s41467-020-15732-9Nature Communications, 2020, vol. 11, núm. 1943cc-by, (c) Bozic et al., 2020info:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by/4.0/oai:repositori.udl.cat:10459.1/684932026-06-24T12:42:17Z
dc.title.none.fl_str_mv Protective role of renal proximal tubular alpha-synuclein in the pathogenesis of kidney fibrosis
title Protective role of renal proximal tubular alpha-synuclein in the pathogenesis of kidney fibrosis
spellingShingle Protective role of renal proximal tubular alpha-synuclein in the pathogenesis of kidney fibrosis
Bozic, Milica
Ronyons -- Fibrosi
title_short Protective role of renal proximal tubular alpha-synuclein in the pathogenesis of kidney fibrosis
title_full Protective role of renal proximal tubular alpha-synuclein in the pathogenesis of kidney fibrosis
title_fullStr Protective role of renal proximal tubular alpha-synuclein in the pathogenesis of kidney fibrosis
title_full_unstemmed Protective role of renal proximal tubular alpha-synuclein in the pathogenesis of kidney fibrosis
title_sort Protective role of renal proximal tubular alpha-synuclein in the pathogenesis of kidney fibrosis
dc.creator.none.fl_str_mv Bozic, Milica
Caus Enríquez, Maite
Rodrigues-Diez, Raul
Pedraza González, Neus
Ruiz-Ortega, Marta
Garí Marsol, Eloi
Gallel Vicente, María del Pilar
Panadés, Maria José
Martínez, Ana
Fernández i Giráldez, Elvira
Valdivielso Revilla, José Manuel
author Bozic, Milica
author_facet Bozic, Milica
Caus Enríquez, Maite
Rodrigues-Diez, Raul
Pedraza González, Neus
Ruiz-Ortega, Marta
Garí Marsol, Eloi
Gallel Vicente, María del Pilar
Panadés, Maria José
Martínez, Ana
Fernández i Giráldez, Elvira
Valdivielso Revilla, José Manuel
author_role author
author2 Caus Enríquez, Maite
Rodrigues-Diez, Raul
Pedraza González, Neus
Ruiz-Ortega, Marta
Garí Marsol, Eloi
Gallel Vicente, María del Pilar
Panadés, Maria José
Martínez, Ana
Fernández i Giráldez, Elvira
Valdivielso Revilla, José Manuel
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Ronyons -- Fibrosi
topic Ronyons -- Fibrosi
description Kidney fibrosis is a highly deleterious process and a final manifestation of chronic kidney disease. Alpha-(α)-synuclein (SNCA) is an actin-binding neuronal protein with various functions within the brain; however, its role in other tissues is unknown. Here, we describe the expression of SNCA in renal epithelial cells and demonstrate its decrease in renal tubules of murine and human fibrotic kidneys, as well as its downregulation in renal proximal tubular epithelial cells (RPTECs) after TGF-β1 treatment. shRNA-mediated knockdown of SNCA in RPTECs results in de novo expression of vimentin and α-SMA, while SNCA overexpression represses TGF-β1-induced mesenchymal markers. Conditional gene silencing of SNCA in RPTECs leads to an exacerbated tubulointerstitial fibrosis (TIF) in two unrelated in vivo fibrotic models, which is associated with an increased activation of MAPK-p38 and PI3K-Akt pathways. Our study provides an evidence that disruption of SNCA signaling in RPTECs contributes to the pathogenesis of renal TIF by facilitating partial epithelial-to-mesenchymal transition and extracellular matrix accumulation.
publishDate 2020
dc.date.none.fl_str_mv 2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://doi.org/10.1038/s41467-020-15732-9
http://hdl.handle.net/10459.1/68493
url https://doi.org/10.1038/s41467-020-15732-9
http://hdl.handle.net/10459.1/68493
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a https://doi.org/10.1038/s41467-020-15732-9
Nature Communications, 2020, vol. 11, núm. 1943
dc.rights.none.fl_str_mv cc-by, (c) Bozic et al., 2020
info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by/4.0/
rights_invalid_str_mv cc-by, (c) Bozic et al., 2020
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv reponame:Repositori Obert UdL
instname:Universitat de Lleida (UdL)
instname_str Universitat de Lleida (UdL)
reponame_str Repositori Obert UdL
collection Repositori Obert UdL
repository.name.fl_str_mv
repository.mail.fl_str_mv
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