Epidermal growth factor receptor/extracellular signal-regulated kinase pathway enhances mineralocorticoid receptor transcriptional activity through protein stabilization

Yuko Mitsuishi, Hirotaka Shibata, Isao Kurihara, Sakiko Kobayashi, Kenichi Yokota, Ayano Takeda, Takeshi Hayashi, Rie Jo, Toshifumi Nakamura, Mitsuha Morisaki, Hiroshi Itoh

Research output: Contribution to journalArticle

Abstract

Activation of mineralocorticoid receptor (MR) is evoked by aldosterone, and it induces hypertension and cardiovascular disease when it's concomitant with excessive salt loading. We have proposed the notion of “MR-associated hypertension”, in which add-on therapy of MR blockers is effective even though serum aldosterone level is within normal range. To elucidate its underlying molecular mechanism, we focused on the effect of epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinase (ERK) activation on MR activity. Epidermal growth factor (EGF) administration increased MR transcriptional activity through EGFR/ERK pathway and increased protein level by counteracting MR ubiquitylation in vitro. EGF administration in vivo also increased MR protein level and target gene expression in kidney, which were decreased by EGFR inhibitor. In addition, the administration of EGFR inhibitor lowered systolic blood pressure and MR activity in DOCA/salt-treated mice. In conclusion, EGFR/ERK pathway activation is considered as one of the underlying mechanisms of aberrant MR activation and EGFR/ERK pathway blockade could be an alternative approach for the prevention of MR-related cardiovascular events.

Original languageEnglish
JournalMolecular and Cellular Endocrinology
DOIs
Publication statusAccepted/In press - 2018 Jan 1

Fingerprint

Mineralocorticoid Receptors
Extracellular Signal-Regulated MAP Kinases
Epidermal Growth Factor Receptor
Stabilization
Proteins
Chemical activation
Aldosterone
Epidermal Growth Factor
Salts
Desoxycorticosterone Acetate
Blood Pressure
Hypertension
Ubiquitination
Blood pressure
Gene expression
Reference Values
Cardiovascular Diseases
Kidney
Gene Expression

Keywords

  • Epidermal growth factor receptor
  • Extracellular signal-regulated kinase pathway
  • Mineralocorticoid receptor

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology

Cite this

@article{567958e11c054263b0d6477ec45b598d,
title = "Epidermal growth factor receptor/extracellular signal-regulated kinase pathway enhances mineralocorticoid receptor transcriptional activity through protein stabilization",
abstract = "Activation of mineralocorticoid receptor (MR) is evoked by aldosterone, and it induces hypertension and cardiovascular disease when it's concomitant with excessive salt loading. We have proposed the notion of “MR-associated hypertension”, in which add-on therapy of MR blockers is effective even though serum aldosterone level is within normal range. To elucidate its underlying molecular mechanism, we focused on the effect of epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinase (ERK) activation on MR activity. Epidermal growth factor (EGF) administration increased MR transcriptional activity through EGFR/ERK pathway and increased protein level by counteracting MR ubiquitylation in vitro. EGF administration in vivo also increased MR protein level and target gene expression in kidney, which were decreased by EGFR inhibitor. In addition, the administration of EGFR inhibitor lowered systolic blood pressure and MR activity in DOCA/salt-treated mice. In conclusion, EGFR/ERK pathway activation is considered as one of the underlying mechanisms of aberrant MR activation and EGFR/ERK pathway blockade could be an alternative approach for the prevention of MR-related cardiovascular events.",
keywords = "Epidermal growth factor receptor, Extracellular signal-regulated kinase pathway, Mineralocorticoid receptor",
author = "Yuko Mitsuishi and Hirotaka Shibata and Isao Kurihara and Sakiko Kobayashi and Kenichi Yokota and Ayano Takeda and Takeshi Hayashi and Rie Jo and Toshifumi Nakamura and Mitsuha Morisaki and Hiroshi Itoh",
year = "2018",
month = "1",
day = "1",
doi = "10.1016/j.mce.2018.01.007",
language = "English",
journal = "Molecular and Cellular Endocrinology",
issn = "0303-7207",
publisher = "Elsevier Ireland Ltd",

}

TY - JOUR

T1 - Epidermal growth factor receptor/extracellular signal-regulated kinase pathway enhances mineralocorticoid receptor transcriptional activity through protein stabilization

AU - Mitsuishi, Yuko

AU - Shibata, Hirotaka

AU - Kurihara, Isao

AU - Kobayashi, Sakiko

AU - Yokota, Kenichi

AU - Takeda, Ayano

AU - Hayashi, Takeshi

AU - Jo, Rie

AU - Nakamura, Toshifumi

AU - Morisaki, Mitsuha

AU - Itoh, Hiroshi

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Activation of mineralocorticoid receptor (MR) is evoked by aldosterone, and it induces hypertension and cardiovascular disease when it's concomitant with excessive salt loading. We have proposed the notion of “MR-associated hypertension”, in which add-on therapy of MR blockers is effective even though serum aldosterone level is within normal range. To elucidate its underlying molecular mechanism, we focused on the effect of epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinase (ERK) activation on MR activity. Epidermal growth factor (EGF) administration increased MR transcriptional activity through EGFR/ERK pathway and increased protein level by counteracting MR ubiquitylation in vitro. EGF administration in vivo also increased MR protein level and target gene expression in kidney, which were decreased by EGFR inhibitor. In addition, the administration of EGFR inhibitor lowered systolic blood pressure and MR activity in DOCA/salt-treated mice. In conclusion, EGFR/ERK pathway activation is considered as one of the underlying mechanisms of aberrant MR activation and EGFR/ERK pathway blockade could be an alternative approach for the prevention of MR-related cardiovascular events.

AB - Activation of mineralocorticoid receptor (MR) is evoked by aldosterone, and it induces hypertension and cardiovascular disease when it's concomitant with excessive salt loading. We have proposed the notion of “MR-associated hypertension”, in which add-on therapy of MR blockers is effective even though serum aldosterone level is within normal range. To elucidate its underlying molecular mechanism, we focused on the effect of epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinase (ERK) activation on MR activity. Epidermal growth factor (EGF) administration increased MR transcriptional activity through EGFR/ERK pathway and increased protein level by counteracting MR ubiquitylation in vitro. EGF administration in vivo also increased MR protein level and target gene expression in kidney, which were decreased by EGFR inhibitor. In addition, the administration of EGFR inhibitor lowered systolic blood pressure and MR activity in DOCA/salt-treated mice. In conclusion, EGFR/ERK pathway activation is considered as one of the underlying mechanisms of aberrant MR activation and EGFR/ERK pathway blockade could be an alternative approach for the prevention of MR-related cardiovascular events.

KW - Epidermal growth factor receptor

KW - Extracellular signal-regulated kinase pathway

KW - Mineralocorticoid receptor

UR - http://www.scopus.com/inward/record.url?scp=85044712012&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85044712012&partnerID=8YFLogxK

U2 - 10.1016/j.mce.2018.01.007

DO - 10.1016/j.mce.2018.01.007

M3 - Article

JO - Molecular and Cellular Endocrinology

JF - Molecular and Cellular Endocrinology

SN - 0303-7207

ER -