Renal inflammation induces salt sensitivity in male db/db mice through dysregulation of ENaC

Autores
Veiras, Luciana Cecilia; Shen, Justin Z. Y.; Bernstein, Ellen A.; Regis, Giovanna C.; Cao, DuoYao; Okwan Duodu, Derick; Khan, Zakir; Gibb, David R.; Dominici, Fernando Pablo; Bernstein, Kenneth E.; Giani, Jorge Fernando
Año de publicación
2021
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Background Hypertension is considered a major risk factor for the progression of diabetic kidney disease. Type 2 diabetes is associated with increased renal sodium reabsorption and salt-sensitive hypertension. Clinical studies show that men have higher risk than premenopausal women for the development of diabetic kidney disease. However, the renal mechanisms that predispose to salt sensitivity during diabetes and whether sexual dimorphism is associated with these mechanisms remains unknown. Methods Female and male db/db mice exposed to a high-salt diet were used to analyze the progression of diabetic kidney disease and the development of hypertension. Results Male, 34-week-old, db/db mice display hypertension when exposed to a 4-week high-salt treatment, whereas equivalently treated female db/db mice remain normotensive. Salt-sensitive hypertension in male mice was associated with no suppression of the epithelial sodium channel (ENaC) in response to a high-salt diet, despite downregulation of several components of the intrarenal renin-angiotensin system. Male db/db mice show higher levels of proinflammatory cytokines and more immune-cell infiltration in the kidney than do female db/db mice. Blocking inflammation, with either mycophenolate mofetil or by reducing IL-6 levels with a neutralizing anti-IL-6 antibody, prevented the development of salt sensitivity in male db/db mice. Conclusions The inflammatory response observed in male, but not in female, db/db mice induces salt-sensitive hypertension by impairing ENaC downregulation in response to high salt. These data provide a mechanistic explanation for the sexual dimorphism associated with the development of diabetic kidney disease and salt sensitivity.
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: Regis, Giovanna C.. Cedars Sinai Medical Center; Estados Unidos
Fil: Cao, DuoYao. Cedars Sinai Medical Center; Estados Unidos
Fil: Okwan Duodu, Derick. Cedars Sinai Medical Center; Estados Unidos
Fil: Khan, Zakir. Cedars Sinai Medical Center; Estados Unidos
Fil: Gibb, David R.. Cedars Sinai Medical Center; Estados Unidos
Fil: Dominici, Fernando Pablo. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; Argentina. 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: Bernstein, Kenneth E.. Cedars Sinai Medical Center; Estados Unidos
Fil: Giani, Jorge Fernando. Cedars Sinai Medical Center; Estados Unidos
Materia
diabetes
renin angiotensin system
sex differences
sodium transporters
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:11336/182921
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/182921
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Renal inflammation induces salt sensitivity in male db/db mice through dysregulation of ENaCVeiras, Luciana CeciliaShen, Justin Z. Y.Bernstein, Ellen A.Regis, Giovanna C.Cao, DuoYaoOkwan Duodu, DerickKhan, ZakirGibb, David R.Dominici, Fernando PabloBernstein, Kenneth E.Giani, Jorge Fernandodiabetesrenin angiotensin systemsex differencessodium transportershttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Background Hypertension is considered a major risk factor for the progression of diabetic kidney disease. Type 2 diabetes is associated with increased renal sodium reabsorption and salt-sensitive hypertension. Clinical studies show that men have higher risk than premenopausal women for the development of diabetic kidney disease. However, the renal mechanisms that predispose to salt sensitivity during diabetes and whether sexual dimorphism is associated with these mechanisms remains unknown. Methods Female and male db/db mice exposed to a high-salt diet were used to analyze the progression of diabetic kidney disease and the development of hypertension. Results Male, 34-week-old, db/db mice display hypertension when exposed to a 4-week high-salt treatment, whereas equivalently treated female db/db mice remain normotensive. Salt-sensitive hypertension in male mice was associated with no suppression of the epithelial sodium channel (ENaC) in response to a high-salt diet, despite downregulation of several components of the intrarenal renin-angiotensin system. Male db/db mice show higher levels of proinflammatory cytokines and more immune-cell infiltration in the kidney than do female db/db mice. Blocking inflammation, with either mycophenolate mofetil or by reducing IL-6 levels with a neutralizing anti-IL-6 antibody, prevented the development of salt sensitivity in male db/db mice. Conclusions The inflammatory response observed in male, but not in female, db/db mice induces salt-sensitive hypertension by impairing ENaC downregulation in response to high salt. These data provide a mechanistic explanation for the sexual dimorphism associated with the development of diabetic kidney disease and salt sensitivity.Fil: 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: Regis, Giovanna C.. Cedars Sinai Medical Center; Estados UnidosFil: Cao, DuoYao. Cedars Sinai Medical Center; Estados UnidosFil: Okwan Duodu, Derick. Cedars Sinai Medical Center; Estados UnidosFil: Khan, Zakir. Cedars Sinai Medical Center; Estados UnidosFil: Gibb, David R.. Cedars Sinai Medical Center; Estados UnidosFil: Dominici, Fernando Pablo. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; Argentina. 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: Bernstein, Kenneth E.. Cedars Sinai Medical Center; Estados UnidosFil: Giani, Jorge Fernando. Cedars Sinai Medical Center; Estados UnidosSynthesis-Stuttgart2021-05info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/vnd.openxmlformats-officedocument.wordprocessingml.documentapplication/pdfhttp://hdl.handle.net/11336/182921Veiras, Luciana Cecilia; Shen, Justin Z. Y.; Bernstein, Ellen A.; Regis, Giovanna C.; Cao, DuoYao; et al.; Renal inflammation induces salt sensitivity in male db/db mice through dysregulation of ENaC; Synthesis-Stuttgart; Journal of the American Society of Nephrology; 32; 5; 5-2021; 1131-11491046-6673CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://jasn.asnjournals.org/lookup/doi/10.1681/ASN.2020081112info:eu-repo/semantics/altIdentifier/doi/10.1681/ASN.2020081112info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:02:47Zoai:ri.conicet.gov.ar:11336/182921instacron: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:34982025-10-22 11:02:47.789CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Renal inflammation induces salt sensitivity in male db/db mice through dysregulation of ENaC
title Renal inflammation induces salt sensitivity in male db/db mice through dysregulation of ENaC
spellingShingle Renal inflammation induces salt sensitivity in male db/db mice through dysregulation of ENaC
Veiras, Luciana Cecilia
diabetes
renin angiotensin system
sex differences
sodium transporters
title_short Renal inflammation induces salt sensitivity in male db/db mice through dysregulation of ENaC
title_full Renal inflammation induces salt sensitivity in male db/db mice through dysregulation of ENaC
title_fullStr Renal inflammation induces salt sensitivity in male db/db mice through dysregulation of ENaC
title_full_unstemmed Renal inflammation induces salt sensitivity in male db/db mice through dysregulation of ENaC
title_sort Renal inflammation induces salt sensitivity in male db/db mice through dysregulation of ENaC
dc.creator.none.fl_str_mv Veiras, Luciana Cecilia
Shen, Justin Z. Y.
Bernstein, Ellen A.
Regis, Giovanna C.
Cao, DuoYao
Okwan Duodu, Derick
Khan, Zakir
Gibb, David R.
Dominici, Fernando Pablo
Bernstein, Kenneth E.
Giani, Jorge Fernando
author Veiras, Luciana Cecilia
author_facet Veiras, Luciana Cecilia
Shen, Justin Z. Y.
Bernstein, Ellen A.
Regis, Giovanna C.
Cao, DuoYao
Okwan Duodu, Derick
Khan, Zakir
Gibb, David R.
Dominici, Fernando Pablo
Bernstein, Kenneth E.
Giani, Jorge Fernando
author_role author
author2 Shen, Justin Z. Y.
Bernstein, Ellen A.
Regis, Giovanna C.
Cao, DuoYao
Okwan Duodu, Derick
Khan, Zakir
Gibb, David R.
Dominici, Fernando Pablo
Bernstein, Kenneth E.
Giani, Jorge Fernando
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv diabetes
renin angiotensin system
sex differences
sodium transporters
topic diabetes
renin angiotensin system
sex differences
sodium transporters
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 Hypertension is considered a major risk factor for the progression of diabetic kidney disease. Type 2 diabetes is associated with increased renal sodium reabsorption and salt-sensitive hypertension. Clinical studies show that men have higher risk than premenopausal women for the development of diabetic kidney disease. However, the renal mechanisms that predispose to salt sensitivity during diabetes and whether sexual dimorphism is associated with these mechanisms remains unknown. Methods Female and male db/db mice exposed to a high-salt diet were used to analyze the progression of diabetic kidney disease and the development of hypertension. Results Male, 34-week-old, db/db mice display hypertension when exposed to a 4-week high-salt treatment, whereas equivalently treated female db/db mice remain normotensive. Salt-sensitive hypertension in male mice was associated with no suppression of the epithelial sodium channel (ENaC) in response to a high-salt diet, despite downregulation of several components of the intrarenal renin-angiotensin system. Male db/db mice show higher levels of proinflammatory cytokines and more immune-cell infiltration in the kidney than do female db/db mice. Blocking inflammation, with either mycophenolate mofetil or by reducing IL-6 levels with a neutralizing anti-IL-6 antibody, prevented the development of salt sensitivity in male db/db mice. Conclusions The inflammatory response observed in male, but not in female, db/db mice induces salt-sensitive hypertension by impairing ENaC downregulation in response to high salt. These data provide a mechanistic explanation for the sexual dimorphism associated with the development of diabetic kidney disease and salt sensitivity.
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: Regis, Giovanna C.. Cedars Sinai Medical Center; Estados Unidos
Fil: Cao, DuoYao. Cedars Sinai Medical Center; Estados Unidos
Fil: Okwan Duodu, Derick. Cedars Sinai Medical Center; Estados Unidos
Fil: Khan, Zakir. Cedars Sinai Medical Center; Estados Unidos
Fil: Gibb, David R.. Cedars Sinai Medical Center; Estados Unidos
Fil: Dominici, Fernando Pablo. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; Argentina. 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: Bernstein, Kenneth E.. Cedars Sinai Medical Center; Estados Unidos
Fil: Giani, Jorge Fernando. Cedars Sinai Medical Center; Estados Unidos
description Background Hypertension is considered a major risk factor for the progression of diabetic kidney disease. Type 2 diabetes is associated with increased renal sodium reabsorption and salt-sensitive hypertension. Clinical studies show that men have higher risk than premenopausal women for the development of diabetic kidney disease. However, the renal mechanisms that predispose to salt sensitivity during diabetes and whether sexual dimorphism is associated with these mechanisms remains unknown. Methods Female and male db/db mice exposed to a high-salt diet were used to analyze the progression of diabetic kidney disease and the development of hypertension. Results Male, 34-week-old, db/db mice display hypertension when exposed to a 4-week high-salt treatment, whereas equivalently treated female db/db mice remain normotensive. Salt-sensitive hypertension in male mice was associated with no suppression of the epithelial sodium channel (ENaC) in response to a high-salt diet, despite downregulation of several components of the intrarenal renin-angiotensin system. Male db/db mice show higher levels of proinflammatory cytokines and more immune-cell infiltration in the kidney than do female db/db mice. Blocking inflammation, with either mycophenolate mofetil or by reducing IL-6 levels with a neutralizing anti-IL-6 antibody, prevented the development of salt sensitivity in male db/db mice. Conclusions The inflammatory response observed in male, but not in female, db/db mice induces salt-sensitive hypertension by impairing ENaC downregulation in response to high salt. These data provide a mechanistic explanation for the sexual dimorphism associated with the development of diabetic kidney disease and salt sensitivity.
publishDate 2021
dc.date.none.fl_str_mv 2021-05
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/11336/182921
Veiras, Luciana Cecilia; Shen, Justin Z. Y.; Bernstein, Ellen A.; Regis, Giovanna C.; Cao, DuoYao; et al.; Renal inflammation induces salt sensitivity in male db/db mice through dysregulation of ENaC; Synthesis-Stuttgart; Journal of the American Society of Nephrology; 32; 5; 5-2021; 1131-1149
1046-6673
CONICET Digital
CONICET
url http://hdl.handle.net/11336/182921
identifier_str_mv Veiras, Luciana Cecilia; Shen, Justin Z. Y.; Bernstein, Ellen A.; Regis, Giovanna C.; Cao, DuoYao; et al.; Renal inflammation induces salt sensitivity in male db/db mice through dysregulation of ENaC; Synthesis-Stuttgart; Journal of the American Society of Nephrology; 32; 5; 5-2021; 1131-1149
1046-6673
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://jasn.asnjournals.org/lookup/doi/10.1681/ASN.2020081112
info:eu-repo/semantics/altIdentifier/doi/10.1681/ASN.2020081112
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/vnd.openxmlformats-officedocument.wordprocessingml.document
application/pdf
dc.publisher.none.fl_str_mv Synthesis-Stuttgart
publisher.none.fl_str_mv Synthesis-Stuttgart
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
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score 12.982451

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