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Eplerenone-Resistant Salt-Sensitive Hypertension in Nedd4-2 C2 KO Mice

The epithelial sodium channel (ENaC) plays critical roles in maintaining fluid and electrolyte homeostasis and is located in the aldosterone-sensitive distal nephron (ASDN). We previously found that Nedd4-2 C2 knockout (KO) mice showed salt-sensitive hypertension with paradoxically enhanced ENaC gen...

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Autores principales: Kino, Tabito, Ishigami, Tomoaki, Murata, Tsumugi, Doi, Hiroshi, Nakashima-Sasaki, Rie, Chen, Lin, Sugiyama, Michiko, Azushima, Kengo, Wakui, Hiromichi, Minegishi, Shintaro, Tamura, Kouichi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5486073/
https://www.ncbi.nlm.nih.gov/pubmed/28604611
http://dx.doi.org/10.3390/ijms18061250
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author Kino, Tabito
Ishigami, Tomoaki
Murata, Tsumugi
Doi, Hiroshi
Nakashima-Sasaki, Rie
Chen, Lin
Sugiyama, Michiko
Azushima, Kengo
Wakui, Hiromichi
Minegishi, Shintaro
Tamura, Kouichi
author_facet Kino, Tabito
Ishigami, Tomoaki
Murata, Tsumugi
Doi, Hiroshi
Nakashima-Sasaki, Rie
Chen, Lin
Sugiyama, Michiko
Azushima, Kengo
Wakui, Hiromichi
Minegishi, Shintaro
Tamura, Kouichi
author_sort Kino, Tabito
collection PubMed
description The epithelial sodium channel (ENaC) plays critical roles in maintaining fluid and electrolyte homeostasis and is located in the aldosterone-sensitive distal nephron (ASDN). We previously found that Nedd4-2 C2 knockout (KO) mice showed salt-sensitive hypertension with paradoxically enhanced ENaC gene expression in ASDN under high oral salt intake. Eplerenone (EPL), a selective aldosterone blocker, is a promising therapeutic option for resistant or/and salt-sensitive hypertension. We examined the effect of EPL on Nedd4-2 C2 KO mice with respect to blood pressure, metabolic parameters, and molecular level changes in ASDN under high oral salt intake. We found that EPL failed to reduce blood pressure in KO mice with high oral salt intake and upregulated ENaC expression in ASDN. Thus, salt-sensitive hypertension in Nedd4-2 C2 KO was EPL-resistant. Gene expression analyses of laser-captured specimens in ASDN suggested the presence of non-aldosterone-dependent activation of ENaC transcription in ASDN of Nedd4-2 C2 KO mice, which was abolished by amiloride treatment. Our results from Nedd4-2 C2 KO mice suggest that enhanced ENaC gene expression is critically involved in salt-sensitive hypertension under certain conditions of specific enzyme isoforms for their ubiquitination.
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spelling pubmed-54860732017-06-29 Eplerenone-Resistant Salt-Sensitive Hypertension in Nedd4-2 C2 KO Mice Kino, Tabito Ishigami, Tomoaki Murata, Tsumugi Doi, Hiroshi Nakashima-Sasaki, Rie Chen, Lin Sugiyama, Michiko Azushima, Kengo Wakui, Hiromichi Minegishi, Shintaro Tamura, Kouichi Int J Mol Sci Article The epithelial sodium channel (ENaC) plays critical roles in maintaining fluid and electrolyte homeostasis and is located in the aldosterone-sensitive distal nephron (ASDN). We previously found that Nedd4-2 C2 knockout (KO) mice showed salt-sensitive hypertension with paradoxically enhanced ENaC gene expression in ASDN under high oral salt intake. Eplerenone (EPL), a selective aldosterone blocker, is a promising therapeutic option for resistant or/and salt-sensitive hypertension. We examined the effect of EPL on Nedd4-2 C2 KO mice with respect to blood pressure, metabolic parameters, and molecular level changes in ASDN under high oral salt intake. We found that EPL failed to reduce blood pressure in KO mice with high oral salt intake and upregulated ENaC expression in ASDN. Thus, salt-sensitive hypertension in Nedd4-2 C2 KO was EPL-resistant. Gene expression analyses of laser-captured specimens in ASDN suggested the presence of non-aldosterone-dependent activation of ENaC transcription in ASDN of Nedd4-2 C2 KO mice, which was abolished by amiloride treatment. Our results from Nedd4-2 C2 KO mice suggest that enhanced ENaC gene expression is critically involved in salt-sensitive hypertension under certain conditions of specific enzyme isoforms for their ubiquitination. MDPI 2017-06-11 /pmc/articles/PMC5486073/ /pubmed/28604611 http://dx.doi.org/10.3390/ijms18061250 Text en © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kino, Tabito
Ishigami, Tomoaki
Murata, Tsumugi
Doi, Hiroshi
Nakashima-Sasaki, Rie
Chen, Lin
Sugiyama, Michiko
Azushima, Kengo
Wakui, Hiromichi
Minegishi, Shintaro
Tamura, Kouichi
Eplerenone-Resistant Salt-Sensitive Hypertension in Nedd4-2 C2 KO Mice
title Eplerenone-Resistant Salt-Sensitive Hypertension in Nedd4-2 C2 KO Mice
title_full Eplerenone-Resistant Salt-Sensitive Hypertension in Nedd4-2 C2 KO Mice
title_fullStr Eplerenone-Resistant Salt-Sensitive Hypertension in Nedd4-2 C2 KO Mice
title_full_unstemmed Eplerenone-Resistant Salt-Sensitive Hypertension in Nedd4-2 C2 KO Mice
title_short Eplerenone-Resistant Salt-Sensitive Hypertension in Nedd4-2 C2 KO Mice
title_sort eplerenone-resistant salt-sensitive hypertension in nedd4-2 c2 ko mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5486073/
https://www.ncbi.nlm.nih.gov/pubmed/28604611
http://dx.doi.org/10.3390/ijms18061250
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