Activation of angiotensin type 2 receptors prevents diabetic complications in female db/db mice by nitric oxide‐mediated mechanisms

Autores
Dominici, Fernando Pablo; Veiras, Luciana Cecilia; Shen, Justin Z.Y.; Bernstein, Ellen A.; Quiroga, Diego Tomás; Steckelings, Ulrike M.; Bernstein, Kenneth E.; Giani, Jorge F.
Año de publicación
2020
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Background and Purpose: The AT2 receptor plays a role in metabolism by opposing the actions triggered by the AT1 receptors. Activation of AT2 receptors has been shown to enhance insulin sensitivity in both normal and insulin resistance animal models. In this study, we investigated the mechanism by which AT2 receptors activation improves metabolism in diabetic mice. Experimental Approach: Female diabetic (db/db) and non-diabetic (db/+) mice were treated for 1 month with the selective AT2 agonist, compound 21 (C21, 0.3 mg·kg−1·day−1, s.c.). To evaluate whether the effects of C21 depend on NO production, a subgroup of mice was treated with C21 plus a sub-pressor dose of the NOS inhibitor l-NAME (0.1 mg·ml−1, drinking water). Key Results: C21-treated db/db mice displayed improved glucose and pyruvate tolerance compared with saline-treated db/db mice. Also, C21-treated db/db mice showed reduced liver weight and decreased hepatic lipid accumulation compared with saline-treated db/db mice. Insulin signalling analysis showed increased phosphorylation of the insulin receptor, Akt and FOXO1 in the livers of C21-treated db/db mice compared with saline-treated counterparts. These findings were associated with increased adiponectin levels in plasma and adipose tissue and reduced adipocyte size in inguinal fat. The beneficial effects of AT2 receptors activation were associated with increased eNOS phosphorylation and higher levels of NO metabolites and were abolished by l-NAME. Conclusion and Implications: Chronic C21 infusion exerts beneficial metabolic effects in female diabetic db/db mice, alleviating type 2 diabetes complications, through a mechanism that involves NO production.
Fil: Dominici, Fernando Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; Argentina
Fil: Veiras, Luciana Cecilia. Cedars Sinai Medical Center; Estados Unidos
Fil: Shen, Justin Z.Y.. Cedars Sinai Medical Center; Estados Unidos
Fil: Bernstein, Ellen A.. Cedars Sinai Medical Center; Estados Unidos
Fil: Quiroga, Diego Tomás. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; Argentina
Fil: Steckelings, Ulrike M.. University of Southern Denmark; Dinamarca
Fil: Bernstein, Kenneth E.. Cedars Sinai Medical Center; Estados Unidos
Fil: Giani, Jorge F.. Cedars Sinai Medical Center; Estados Unidos
Materia
AKT
ANGIOTENSIN TYPE 2 RECEPTOR
DB/DB MICE
FOXO1
GLUCONEOGENESIS
INSULIN RECEPTOR
RENIN–ANGIOTENSIN SYSTEM
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/149575
Acceder
id CONICETDig_af9cc893b2a37b61e0de5bb575f039b1
oai_identifier_str oai:ri.conicet.gov.ar:11336/149575
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Activation of angiotensin type 2 receptors prevents diabetic complications in female db/db mice by nitric oxide‐mediated mechanismsDominici, Fernando PabloVeiras, Luciana CeciliaShen, Justin Z.Y.Bernstein, Ellen A.Quiroga, Diego TomásSteckelings, Ulrike M.Bernstein, Kenneth E.Giani, Jorge F.AKTANGIOTENSIN TYPE 2 RECEPTORDB/DB MICEFOXO1GLUCONEOGENESISINSULIN RECEPTORRENIN–ANGIOTENSIN SYSTEMhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Background and Purpose: The AT2 receptor plays a role in metabolism by opposing the actions triggered by the AT1 receptors. Activation of AT2 receptors has been shown to enhance insulin sensitivity in both normal and insulin resistance animal models. In this study, we investigated the mechanism by which AT2 receptors activation improves metabolism in diabetic mice. Experimental Approach: Female diabetic (db/db) and non-diabetic (db/+) mice were treated for 1 month with the selective AT2 agonist, compound 21 (C21, 0.3 mg·kg−1·day−1, s.c.). To evaluate whether the effects of C21 depend on NO production, a subgroup of mice was treated with C21 plus a sub-pressor dose of the NOS inhibitor l-NAME (0.1 mg·ml−1, drinking water). Key Results: C21-treated db/db mice displayed improved glucose and pyruvate tolerance compared with saline-treated db/db mice. Also, C21-treated db/db mice showed reduced liver weight and decreased hepatic lipid accumulation compared with saline-treated db/db mice. Insulin signalling analysis showed increased phosphorylation of the insulin receptor, Akt and FOXO1 in the livers of C21-treated db/db mice compared with saline-treated counterparts. These findings were associated with increased adiponectin levels in plasma and adipose tissue and reduced adipocyte size in inguinal fat. The beneficial effects of AT2 receptors activation were associated with increased eNOS phosphorylation and higher levels of NO metabolites and were abolished by l-NAME. Conclusion and Implications: Chronic C21 infusion exerts beneficial metabolic effects in female diabetic db/db mice, alleviating type 2 diabetes complications, through a mechanism that involves NO production.Fil: Dominici, Fernando Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Veiras, Luciana Cecilia. Cedars Sinai Medical Center; Estados UnidosFil: Shen, Justin Z.Y.. Cedars Sinai Medical Center; Estados UnidosFil: Bernstein, Ellen A.. Cedars Sinai Medical Center; Estados UnidosFil: Quiroga, Diego Tomás. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Steckelings, Ulrike M.. University of Southern Denmark; DinamarcaFil: Bernstein, Kenneth E.. Cedars Sinai Medical Center; Estados UnidosFil: Giani, Jorge F.. Cedars Sinai Medical Center; Estados UnidosWiley Blackwell Publishing, Inc2020-08info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/149575Dominici, Fernando Pablo; Veiras, Luciana Cecilia; Shen, Justin Z.Y.; Bernstein, Ellen A.; Quiroga, Diego Tomás; et al.; Activation of angiotensin type 2 receptors prevents diabetic complications in female db/db mice by nitric oxide‐mediated mechanisms; Wiley Blackwell Publishing, Inc; British Journal of Pharmacology; 177; 20; 8-2020; 4766-47810007-1188CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://onlinelibrary.wiley.com/doi/abs/10.1111/bph.15241info:eu-repo/semantics/altIdentifier/doi/10.1111/bph.15241info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:07:47Zoai:ri.conicet.gov.ar:11336/149575instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 10:07:47.313CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Activation of angiotensin type 2 receptors prevents diabetic complications in female db/db mice by nitric oxide‐mediated mechanisms
title Activation of angiotensin type 2 receptors prevents diabetic complications in female db/db mice by nitric oxide‐mediated mechanisms
spellingShingle Activation of angiotensin type 2 receptors prevents diabetic complications in female db/db mice by nitric oxide‐mediated mechanisms
Dominici, Fernando Pablo
AKT
ANGIOTENSIN TYPE 2 RECEPTOR
DB/DB MICE
FOXO1
GLUCONEOGENESIS
INSULIN RECEPTOR
RENIN–ANGIOTENSIN SYSTEM
title_short Activation of angiotensin type 2 receptors prevents diabetic complications in female db/db mice by nitric oxide‐mediated mechanisms
title_full Activation of angiotensin type 2 receptors prevents diabetic complications in female db/db mice by nitric oxide‐mediated mechanisms
title_fullStr Activation of angiotensin type 2 receptors prevents diabetic complications in female db/db mice by nitric oxide‐mediated mechanisms
title_full_unstemmed Activation of angiotensin type 2 receptors prevents diabetic complications in female db/db mice by nitric oxide‐mediated mechanisms
title_sort Activation of angiotensin type 2 receptors prevents diabetic complications in female db/db mice by nitric oxide‐mediated mechanisms
dc.creator.none.fl_str_mv Dominici, Fernando Pablo
Veiras, Luciana Cecilia
Shen, Justin Z.Y.
Bernstein, Ellen A.
Quiroga, Diego Tomás
Steckelings, Ulrike M.
Bernstein, Kenneth E.
Giani, Jorge F.
author Dominici, Fernando Pablo
author_facet Dominici, Fernando Pablo
Veiras, Luciana Cecilia
Shen, Justin Z.Y.
Bernstein, Ellen A.
Quiroga, Diego Tomás
Steckelings, Ulrike M.
Bernstein, Kenneth E.
Giani, Jorge F.
author_role author
author2 Veiras, Luciana Cecilia
Shen, Justin Z.Y.
Bernstein, Ellen A.
Quiroga, Diego Tomás
Steckelings, Ulrike M.
Bernstein, Kenneth E.
Giani, Jorge F.
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv AKT
ANGIOTENSIN TYPE 2 RECEPTOR
DB/DB MICE
FOXO1
GLUCONEOGENESIS
INSULIN RECEPTOR
RENIN–ANGIOTENSIN SYSTEM
topic AKT
ANGIOTENSIN TYPE 2 RECEPTOR
DB/DB MICE
FOXO1
GLUCONEOGENESIS
INSULIN RECEPTOR
RENIN–ANGIOTENSIN SYSTEM
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Background and Purpose: The AT2 receptor plays a role in metabolism by opposing the actions triggered by the AT1 receptors. Activation of AT2 receptors has been shown to enhance insulin sensitivity in both normal and insulin resistance animal models. In this study, we investigated the mechanism by which AT2 receptors activation improves metabolism in diabetic mice. Experimental Approach: Female diabetic (db/db) and non-diabetic (db/+) mice were treated for 1 month with the selective AT2 agonist, compound 21 (C21, 0.3 mg·kg−1·day−1, s.c.). To evaluate whether the effects of C21 depend on NO production, a subgroup of mice was treated with C21 plus a sub-pressor dose of the NOS inhibitor l-NAME (0.1 mg·ml−1, drinking water). Key Results: C21-treated db/db mice displayed improved glucose and pyruvate tolerance compared with saline-treated db/db mice. Also, C21-treated db/db mice showed reduced liver weight and decreased hepatic lipid accumulation compared with saline-treated db/db mice. Insulin signalling analysis showed increased phosphorylation of the insulin receptor, Akt and FOXO1 in the livers of C21-treated db/db mice compared with saline-treated counterparts. These findings were associated with increased adiponectin levels in plasma and adipose tissue and reduced adipocyte size in inguinal fat. The beneficial effects of AT2 receptors activation were associated with increased eNOS phosphorylation and higher levels of NO metabolites and were abolished by l-NAME. Conclusion and Implications: Chronic C21 infusion exerts beneficial metabolic effects in female diabetic db/db mice, alleviating type 2 diabetes complications, through a mechanism that involves NO production.
Fil: Dominici, Fernando Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; Argentina
Fil: Veiras, Luciana Cecilia. Cedars Sinai Medical Center; Estados Unidos
Fil: Shen, Justin Z.Y.. Cedars Sinai Medical Center; Estados Unidos
Fil: Bernstein, Ellen A.. Cedars Sinai Medical Center; Estados Unidos
Fil: Quiroga, Diego Tomás. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; Argentina
Fil: Steckelings, Ulrike M.. University of Southern Denmark; Dinamarca
Fil: Bernstein, Kenneth E.. Cedars Sinai Medical Center; Estados Unidos
Fil: Giani, Jorge F.. Cedars Sinai Medical Center; Estados Unidos
description Background and Purpose: The AT2 receptor plays a role in metabolism by opposing the actions triggered by the AT1 receptors. Activation of AT2 receptors has been shown to enhance insulin sensitivity in both normal and insulin resistance animal models. In this study, we investigated the mechanism by which AT2 receptors activation improves metabolism in diabetic mice. Experimental Approach: Female diabetic (db/db) and non-diabetic (db/+) mice were treated for 1 month with the selective AT2 agonist, compound 21 (C21, 0.3 mg·kg−1·day−1, s.c.). To evaluate whether the effects of C21 depend on NO production, a subgroup of mice was treated with C21 plus a sub-pressor dose of the NOS inhibitor l-NAME (0.1 mg·ml−1, drinking water). Key Results: C21-treated db/db mice displayed improved glucose and pyruvate tolerance compared with saline-treated db/db mice. Also, C21-treated db/db mice showed reduced liver weight and decreased hepatic lipid accumulation compared with saline-treated db/db mice. Insulin signalling analysis showed increased phosphorylation of the insulin receptor, Akt and FOXO1 in the livers of C21-treated db/db mice compared with saline-treated counterparts. These findings were associated with increased adiponectin levels in plasma and adipose tissue and reduced adipocyte size in inguinal fat. The beneficial effects of AT2 receptors activation were associated with increased eNOS phosphorylation and higher levels of NO metabolites and were abolished by l-NAME. Conclusion and Implications: Chronic C21 infusion exerts beneficial metabolic effects in female diabetic db/db mice, alleviating type 2 diabetes complications, through a mechanism that involves NO production.
publishDate 2020
dc.date.none.fl_str_mv 2020-08
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/149575
Dominici, Fernando Pablo; Veiras, Luciana Cecilia; Shen, Justin Z.Y.; Bernstein, Ellen A.; Quiroga, Diego Tomás; et al.; Activation of angiotensin type 2 receptors prevents diabetic complications in female db/db mice by nitric oxide‐mediated mechanisms; Wiley Blackwell Publishing, Inc; British Journal of Pharmacology; 177; 20; 8-2020; 4766-4781
0007-1188
CONICET Digital
CONICET
url http://hdl.handle.net/11336/149575
identifier_str_mv Dominici, Fernando Pablo; Veiras, Luciana Cecilia; Shen, Justin Z.Y.; Bernstein, Ellen A.; Quiroga, Diego Tomás; et al.; Activation of angiotensin type 2 receptors prevents diabetic complications in female db/db mice by nitric oxide‐mediated mechanisms; Wiley Blackwell Publishing, Inc; British Journal of Pharmacology; 177; 20; 8-2020; 4766-4781
0007-1188
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://onlinelibrary.wiley.com/doi/abs/10.1111/bph.15241
info:eu-repo/semantics/altIdentifier/doi/10.1111/bph.15241
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Wiley Blackwell Publishing, Inc
publisher.none.fl_str_mv Wiley Blackwell Publishing, Inc
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1842270017664581632
score 13.13397

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