VEGFR2 blockade improves renal damage in an experimental model of type 2 diabetic nephropathy

The absence of optimal treatments for Diabetic Nephropathy (DN) highlights the importance of the search for novel therapeutic targets. The vascular endothelial growth factor receptor 2 (VEGFR2) pathway is activated in experimental and human DN, but the e ects of its blockade in experimental models o...

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Autores: Lavoz, Carolina, Rodrigues-Diez, Raul R., Plaza, Anita, Carpio, Daniel, Egido de los Ríos, Jesús, Ruiz Ortega, Marta, Mezzano, Sergio
Tipo de recurso: artículo
Fecha de publicación:2020
País:España
Institución:Universidad Autónoma de Madrid
Repositorio:Biblos-e Archivo. Repositorio Institucional de la UAM
Idioma:inglés
OAI Identifier:oai:repositorio.uam.es:10486/693063
Acceso en línea:http://hdl.handle.net/10486/693063
https://dx.doi.org/10.3390/jcm9020302
Access Level:acceso abierto
Palabra clave:VEGFR2
VEGFA
GREMLIN
Inflammation
Podocytes
Diabetes
Diabetic nephropathy
Tubular cells
Medicina
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spelling VEGFR2 blockade improves renal damage in an experimental model of type 2 diabetic nephropathyLavoz, CarolinaRodrigues-Diez, Raul R.Plaza, AnitaCarpio, DanielEgido de los Ríos, JesúsRuiz Ortega, MartaMezzano, SergioVEGFR2VEGFAGREMLINInflammationPodocytesDiabetesDiabetic nephropathyTubular cellsMedicinaThe absence of optimal treatments for Diabetic Nephropathy (DN) highlights the importance of the search for novel therapeutic targets. The vascular endothelial growth factor receptor 2 (VEGFR2) pathway is activated in experimental and human DN, but the e ects of its blockade in experimental models of DN is still controversial. Here, we test the e ects of a therapeutic anti-VEGFR2 treatment, using a VEGFR2 kinase inhibitor, on the progression of renal damage in the BTBR ob/ob (leptin deficiency mutation) mice. This experimental diabetic model develops histological characteristics mimicking the key features of advanced human DN. A VEGFR2 pathway-activation blockade using the VEGFR2 kinase inhibitor SU5416, starting after kidney disease development, improves renal function, glomerular damage (mesangial matrix expansion and basement membrane thickening), tubulointerstitial inflammation and tubular atrophy, compared to untreated diabetic mice. The downstream mechanisms involved in these beneficial e ects of VEGFR2 blockade include gene expression restoration of podocyte markers and downregulation of renal injury biomarkers and pro-inflammatory mediators. Several ligands can activate VEGFR2, including the canonical ligands VEGFs and GREMLIN. Activation of a GREMLIN/VEGFR2 pathway, but not other ligands, is correlated with renal damage progression in BTBR ob/ob diabetic mice. RNA sequencing analysis of GREMLIN-regulated genes confirm the modulation of proinflammatory genes and related-molecular pathways. Overall, these data show that a GREMLIN/VEGFR2 pathway activation is involved in diabetic kidney disease and could potentially be a novel therapeutic target in this clinical conditionThis research was funded by Fondecyt 1160465 to S.M., e Instituto de Salud Carlos III (ISCIII) and Fondos FEDER European Union (Grants PI17/00119 and Red de Investigación Renal REDINREN: RD16/0009 to M.R.-O; and PI17/01495 to J.E.). Comunidad de Madrid (Grant “NOVELREN” B2017/BMD-3751 to M.R.-O).MDPI, Basel, SwitzerlandDepartamento de MedicinaFacultad de MedicinaInstituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD)20202020-01-21research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10486/693063https://dx.doi.org/10.3390/jcm9020302reponame:Biblos-e Archivo. Repositorio Institucional de la UAMinstname:Universidad Autónoma de MadridInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:repositorio.uam.es:10486/6930632026-06-23T12:46:27Z
dc.title.none.fl_str_mv VEGFR2 blockade improves renal damage in an experimental model of type 2 diabetic nephropathy
title VEGFR2 blockade improves renal damage in an experimental model of type 2 diabetic nephropathy
spellingShingle VEGFR2 blockade improves renal damage in an experimental model of type 2 diabetic nephropathy
Lavoz, Carolina
VEGFR2
VEGFA
GREMLIN
Inflammation
Podocytes
Diabetes
Diabetic nephropathy
Tubular cells
Medicina
title_short VEGFR2 blockade improves renal damage in an experimental model of type 2 diabetic nephropathy
title_full VEGFR2 blockade improves renal damage in an experimental model of type 2 diabetic nephropathy
title_fullStr VEGFR2 blockade improves renal damage in an experimental model of type 2 diabetic nephropathy
title_full_unstemmed VEGFR2 blockade improves renal damage in an experimental model of type 2 diabetic nephropathy
title_sort VEGFR2 blockade improves renal damage in an experimental model of type 2 diabetic nephropathy
dc.creator.none.fl_str_mv Lavoz, Carolina
Rodrigues-Diez, Raul R.
Plaza, Anita
Carpio, Daniel
Egido de los Ríos, Jesús
Ruiz Ortega, Marta
Mezzano, Sergio
author Lavoz, Carolina
author_facet Lavoz, Carolina
Rodrigues-Diez, Raul R.
Plaza, Anita
Carpio, Daniel
Egido de los Ríos, Jesús
Ruiz Ortega, Marta
Mezzano, Sergio
author_role author
author2 Rodrigues-Diez, Raul R.
Plaza, Anita
Carpio, Daniel
Egido de los Ríos, Jesús
Ruiz Ortega, Marta
Mezzano, Sergio
author2_role author
author
author
author
author
author
dc.contributor.none.fl_str_mv Departamento de Medicina
Facultad de Medicina
Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD)
dc.subject.none.fl_str_mv VEGFR2
VEGFA
GREMLIN
Inflammation
Podocytes
Diabetes
Diabetic nephropathy
Tubular cells
Medicina
topic VEGFR2
VEGFA
GREMLIN
Inflammation
Podocytes
Diabetes
Diabetic nephropathy
Tubular cells
Medicina
description The absence of optimal treatments for Diabetic Nephropathy (DN) highlights the importance of the search for novel therapeutic targets. The vascular endothelial growth factor receptor 2 (VEGFR2) pathway is activated in experimental and human DN, but the e ects of its blockade in experimental models of DN is still controversial. Here, we test the e ects of a therapeutic anti-VEGFR2 treatment, using a VEGFR2 kinase inhibitor, on the progression of renal damage in the BTBR ob/ob (leptin deficiency mutation) mice. This experimental diabetic model develops histological characteristics mimicking the key features of advanced human DN. A VEGFR2 pathway-activation blockade using the VEGFR2 kinase inhibitor SU5416, starting after kidney disease development, improves renal function, glomerular damage (mesangial matrix expansion and basement membrane thickening), tubulointerstitial inflammation and tubular atrophy, compared to untreated diabetic mice. The downstream mechanisms involved in these beneficial e ects of VEGFR2 blockade include gene expression restoration of podocyte markers and downregulation of renal injury biomarkers and pro-inflammatory mediators. Several ligands can activate VEGFR2, including the canonical ligands VEGFs and GREMLIN. Activation of a GREMLIN/VEGFR2 pathway, but not other ligands, is correlated with renal damage progression in BTBR ob/ob diabetic mice. RNA sequencing analysis of GREMLIN-regulated genes confirm the modulation of proinflammatory genes and related-molecular pathways. Overall, these data show that a GREMLIN/VEGFR2 pathway activation is involved in diabetic kidney disease and could potentially be a novel therapeutic target in this clinical condition
publishDate 2020
dc.date.none.fl_str_mv 2020
2020-01-21
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10486/693063
https://dx.doi.org/10.3390/jcm9020302
url http://hdl.handle.net/10486/693063
https://dx.doi.org/10.3390/jcm9020302
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv MDPI, Basel, Switzerland
publisher.none.fl_str_mv MDPI, Basel, Switzerland
dc.source.none.fl_str_mv reponame:Biblos-e Archivo. Repositorio Institucional de la UAM
instname:Universidad Autónoma de Madrid
instname_str Universidad Autónoma de Madrid
reponame_str Biblos-e Archivo. Repositorio Institucional de la UAM
collection Biblos-e Archivo. Repositorio Institucional de la UAM
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.301603

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