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
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/182921
Ver los metadatos del registro completo
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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 Técnicas2025-09-29T09:34:45Zoai: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:34982025-09-29 09:34:46.105CONICET 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 |
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info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
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openAccess |
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https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
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Synthesis-Stuttgart |
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Synthesis-Stuttgart |
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reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas |
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CONICET Digital (CONICET) |
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Consejo Nacional de Investigaciones Científicas y Técnicas |
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CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas |
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dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar |
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