The protective role of peroxisome proliferator-activated receptor gamma in lipotoxic podocytes

Podocytes are specialized epithelial cells that maintain the glomerular filtration barrier. These cells are susceptible to lipotoxicity in the obese state and irreversibly lost during kidney disease leading to proteinuria and renal injury. PPARγ is a nuclear receptor whose activation can be renoprot...

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Autores: Carrasco, Almudena G., Izquierdo Lahuerta, Adriana, Valverde, Ángela M., Ni, Lan, Flores-Salguero, Elena, Coward, R. J., Medina, Gema
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/341210
Acceso en línea:http://hdl.handle.net/10261/341210
Access Level:acceso abierto
Palabra clave:PPARgamma
RXR
Lipid droplets
TZD
Bexarotene
Podocyte
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spelling The protective role of peroxisome proliferator-activated receptor gamma in lipotoxic podocytesCarrasco, Almudena G.Izquierdo Lahuerta, AdrianaValverde, Ángela M.Ni, LanFlores-Salguero, ElenaCoward, R. J.Medina, GemaPPARgammaRXRLipid dropletsTZDBexarotenePodocytePodocytes are specialized epithelial cells that maintain the glomerular filtration barrier. These cells are susceptible to lipotoxicity in the obese state and irreversibly lost during kidney disease leading to proteinuria and renal injury. PPARγ is a nuclear receptor whose activation can be renoprotective. This study examined the role of PPARγ in the lipotoxic podocyte using a PPARγ knockout (PPARγKO) cell line and since the activation of PPARγ by Thiazolidinediones (TZD) is limited by their side effects, it explored other alternative therapies to prevent podocyte lipotoxic damage. Wild-type and PPARγKO podocytes were exposed to the fatty acid palmitic acid (PA) and treated with the TZD (Pioglitazone) and/or the Retinoid X receptor (RXR) agonist Bexarotene (BX). It revealed that podocyte PPARγ is essential for podocyte function. PPARγ deletion reduced key podocyte proteins including podocin and nephrin while increasing basal levels of oxidative and ER stress causing apoptosis and cell death. A combination therapy of low-dose TZD and BX activated both the PPARγ and RXR receptors reducing PA-induced podocyte damage. This study confirms the crucial role of PPARγ in podocyte biology and that their activation in combination therapy of TZD and BX may be beneficial in the treatment of obesity-related kidney disease.Research conducted for this publication was supported by the Mobility stays abroad José Castillejo for young doctors of Ministerio de Educación Cultura y Deporte de España [CAS 12/00160], Ministerio de Economía y Competitividad de España [BFU2016-78951-R, BFU2017-90578-REDT], Ministerio de Ciencia e Innovacion [PID2020-116875RB-I00], Comunidad de Madrid (Spain) [S2017/BMD-3684, P2022/BMD-7227]. RJC was supported by the British Medical Research Council (MRC) with a Senior Clinical Fellowship [MR/K010492/1].Peer reviewedElsevier BVMinisterio de Educación, Cultura y Deporte (España)Ministerio de Economía y Competitividad (España)Ministerio de Ciencia e Innovación (España)Agencia Estatal de Investigación (España)Comunidad de MadridBritish Medical AssociationConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2023202320232023info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/341210reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI//BFU2016-78951-Rinfo:eu-repo/grantAgreement/MINECO//BFU2017-90578-REDTinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-116875RB-I00S2017/BMD-3684/MOIR2-CMP2022/BMD-7227/MOIR-ACTOME-CMhttp://dx.doi.org/10.1016/j.bbalip.2023.159329Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3412102026-05-22T06:33:51Z
dc.title.none.fl_str_mv The protective role of peroxisome proliferator-activated receptor gamma in lipotoxic podocytes
title The protective role of peroxisome proliferator-activated receptor gamma in lipotoxic podocytes
spellingShingle The protective role of peroxisome proliferator-activated receptor gamma in lipotoxic podocytes
Carrasco, Almudena G.
PPARgamma
RXR
Lipid droplets
TZD
Bexarotene
Podocyte
title_short The protective role of peroxisome proliferator-activated receptor gamma in lipotoxic podocytes
title_full The protective role of peroxisome proliferator-activated receptor gamma in lipotoxic podocytes
title_fullStr The protective role of peroxisome proliferator-activated receptor gamma in lipotoxic podocytes
title_full_unstemmed The protective role of peroxisome proliferator-activated receptor gamma in lipotoxic podocytes
title_sort The protective role of peroxisome proliferator-activated receptor gamma in lipotoxic podocytes
dc.creator.none.fl_str_mv Carrasco, Almudena G.
Izquierdo Lahuerta, Adriana
Valverde, Ángela M.
Ni, Lan
Flores-Salguero, Elena
Coward, R. J.
Medina, Gema
author Carrasco, Almudena G.
author_facet Carrasco, Almudena G.
Izquierdo Lahuerta, Adriana
Valverde, Ángela M.
Ni, Lan
Flores-Salguero, Elena
Coward, R. J.
Medina, Gema
author_role author
author2 Izquierdo Lahuerta, Adriana
Valverde, Ángela M.
Ni, Lan
Flores-Salguero, Elena
Coward, R. J.
Medina, Gema
author2_role author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Educación, Cultura y Deporte (España)
Ministerio de Economía y Competitividad (España)
Ministerio de Ciencia e Innovación (España)
Agencia Estatal de Investigación (España)
Comunidad de Madrid
British Medical Association
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv PPARgamma
RXR
Lipid droplets
TZD
Bexarotene
Podocyte
topic PPARgamma
RXR
Lipid droplets
TZD
Bexarotene
Podocyte
description Podocytes are specialized epithelial cells that maintain the glomerular filtration barrier. These cells are susceptible to lipotoxicity in the obese state and irreversibly lost during kidney disease leading to proteinuria and renal injury. PPARγ is a nuclear receptor whose activation can be renoprotective. This study examined the role of PPARγ in the lipotoxic podocyte using a PPARγ knockout (PPARγKO) cell line and since the activation of PPARγ by Thiazolidinediones (TZD) is limited by their side effects, it explored other alternative therapies to prevent podocyte lipotoxic damage. Wild-type and PPARγKO podocytes were exposed to the fatty acid palmitic acid (PA) and treated with the TZD (Pioglitazone) and/or the Retinoid X receptor (RXR) agonist Bexarotene (BX). It revealed that podocyte PPARγ is essential for podocyte function. PPARγ deletion reduced key podocyte proteins including podocin and nephrin while increasing basal levels of oxidative and ER stress causing apoptosis and cell death. A combination therapy of low-dose TZD and BX activated both the PPARγ and RXR receptors reducing PA-induced podocyte damage. This study confirms the crucial role of PPARγ in podocyte biology and that their activation in combination therapy of TZD and BX may be beneficial in the treatment of obesity-related kidney disease.
publishDate 2023
dc.date.none.fl_str_mv 2023
2023
2023
2023
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/341210
url http://hdl.handle.net/10261/341210
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/AEI//BFU2016-78951-R
info:eu-repo/grantAgreement/MINECO//BFU2017-90578-REDT
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-116875RB-I00
S2017/BMD-3684/MOIR2-CM
P2022/BMD-7227/MOIR-ACTOME-CM
http://dx.doi.org/10.1016/j.bbalip.2023.159329
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier BV
publisher.none.fl_str_mv Elsevier BV
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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