Aldosterone suppresses insulin signaling via the downregulation of insulin receptor substrate-1 in vascular smooth muscle cells

Hirofumi Hitomi, Hideyasu Kiyomoto, Akira Nishiyama, Taiga Hara, Kumiko Moriwaki, Kumiko Kaifu, Genei Ihara, Yoshiko Fujita, Toyomu Ugawa, Masakazu Kohno

Research output: Contribution to journalArticle

110 Citations (Scopus)

Abstract

Clinical reports indicate that patients with primary aldosteronism commonly have impaired glucose tolerance; however, the relationship between aldosterone and insulin signaling pathway has not been clarified. In this study, we examined the effects of aldosterone treatment on insulin receptor substrate-1 expression and insulin signaling pathway including Akt phosphorylation and glucose uptake in rat vascular smooth muscle cells. Insulin receptor substrate-1 protein expression and Akt phosphorylation were determined by Western blot analysis with anti-insulin receptor substrate-1 and phosphorylated-Akt antibodies, respectively. Glucose metabolism was evaluated using H-labeled 2-deoxy-d-glucose uptake. Aldosterone (1-100 nmol/L) dose-dependently decreased insulin receptor substrate-1 protein expression with a peak at 18 hours (n=4). Aldosterone-induced degradation of insulin receptor substrate-1 was markedly attenuated by treatment with the selective mineralocorticoid receptor antagonist eplerenone (10 μmol/L; n=4). Furthermore, degradation was blocked by the Src inhibitor PP1 (20 μmol/L; n=4). Treatment with antioxidants, N-acetylcysteine (10 mmol/L), or ebselen (40 μmol/L) also attenuated aldosterone-induced insulin receptor substrate-1 degradation (n=4). In addition, proteasome inhibitor MG132 (1 μmol/L) prevented insulin receptor substrate-1 degradation (n=4). Aldosterone treatment abolished insulin-induced Akt phosphorylation (100 nmol/L; 5 minutes; n=4). Furthermore, aldosterone pretreatment decreased insulin-stimulated (100 nmol/L; 60 minutes; n=4) glucose uptake by 50%, which was reversed by eplerenone (10 μmol/L; n=4). These data indicate that aldosterone decreases insulin receptor substrate-1 expression via Src and reactive oxygen species stimulation by proteasome-dependent degradation in vascular smooth muscle cells; thus, aldosterone may be involved in the pathogenesis of vascular insulin resistance via oxidative stress.

Original languageEnglish
Pages (from-to)750-755
Number of pages6
JournalHypertension
Volume50
Issue number4
DOIs
Publication statusPublished - Oct 2007
Externally publishedYes

Fingerprint

Insulin Receptor Substrate Proteins
Aldosterone
Vascular Smooth Muscle
Smooth Muscle Myocytes
Down-Regulation
Insulin
Glucose
Phosphorylation
Mineralocorticoid Receptor Antagonists
Hyperaldosteronism
Proteasome Inhibitors
Glucose Intolerance
Acetylcysteine
Proteasome Endopeptidase Complex
Therapeutics
Vascular Resistance
Insulin Resistance
Reactive Oxygen Species
Oxidative Stress
Antioxidants

Keywords

  • Aldosterone
  • Eplerenone
  • Insulin receptor substrate-1
  • Insulin resistance
  • Metabolic syndrome
  • Oxidative stress
  • Type 2 diabetes mellitus

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Aldosterone suppresses insulin signaling via the downregulation of insulin receptor substrate-1 in vascular smooth muscle cells. / Hitomi, Hirofumi; Kiyomoto, Hideyasu; Nishiyama, Akira; Hara, Taiga; Moriwaki, Kumiko; Kaifu, Kumiko; Ihara, Genei; Fujita, Yoshiko; Ugawa, Toyomu; Kohno, Masakazu.

In: Hypertension, Vol. 50, No. 4, 10.2007, p. 750-755.

Research output: Contribution to journalArticle

Hitomi, H, Kiyomoto, H, Nishiyama, A, Hara, T, Moriwaki, K, Kaifu, K, Ihara, G, Fujita, Y, Ugawa, T & Kohno, M 2007, 'Aldosterone suppresses insulin signaling via the downregulation of insulin receptor substrate-1 in vascular smooth muscle cells', Hypertension, vol. 50, no. 4, pp. 750-755. https://doi.org/10.1161/HYPERTENSIONAHA.107.093955
Hitomi, Hirofumi ; Kiyomoto, Hideyasu ; Nishiyama, Akira ; Hara, Taiga ; Moriwaki, Kumiko ; Kaifu, Kumiko ; Ihara, Genei ; Fujita, Yoshiko ; Ugawa, Toyomu ; Kohno, Masakazu. / Aldosterone suppresses insulin signaling via the downregulation of insulin receptor substrate-1 in vascular smooth muscle cells. In: Hypertension. 2007 ; Vol. 50, No. 4. pp. 750-755.
@article{acdb4e8104c74d60b2ce3d4f1b26f339,
title = "Aldosterone suppresses insulin signaling via the downregulation of insulin receptor substrate-1 in vascular smooth muscle cells",
abstract = "Clinical reports indicate that patients with primary aldosteronism commonly have impaired glucose tolerance; however, the relationship between aldosterone and insulin signaling pathway has not been clarified. In this study, we examined the effects of aldosterone treatment on insulin receptor substrate-1 expression and insulin signaling pathway including Akt phosphorylation and glucose uptake in rat vascular smooth muscle cells. Insulin receptor substrate-1 protein expression and Akt phosphorylation were determined by Western blot analysis with anti-insulin receptor substrate-1 and phosphorylated-Akt antibodies, respectively. Glucose metabolism was evaluated using H-labeled 2-deoxy-d-glucose uptake. Aldosterone (1-100 nmol/L) dose-dependently decreased insulin receptor substrate-1 protein expression with a peak at 18 hours (n=4). Aldosterone-induced degradation of insulin receptor substrate-1 was markedly attenuated by treatment with the selective mineralocorticoid receptor antagonist eplerenone (10 μmol/L; n=4). Furthermore, degradation was blocked by the Src inhibitor PP1 (20 μmol/L; n=4). Treatment with antioxidants, N-acetylcysteine (10 mmol/L), or ebselen (40 μmol/L) also attenuated aldosterone-induced insulin receptor substrate-1 degradation (n=4). In addition, proteasome inhibitor MG132 (1 μmol/L) prevented insulin receptor substrate-1 degradation (n=4). Aldosterone treatment abolished insulin-induced Akt phosphorylation (100 nmol/L; 5 minutes; n=4). Furthermore, aldosterone pretreatment decreased insulin-stimulated (100 nmol/L; 60 minutes; n=4) glucose uptake by 50{\%}, which was reversed by eplerenone (10 μmol/L; n=4). These data indicate that aldosterone decreases insulin receptor substrate-1 expression via Src and reactive oxygen species stimulation by proteasome-dependent degradation in vascular smooth muscle cells; thus, aldosterone may be involved in the pathogenesis of vascular insulin resistance via oxidative stress.",
keywords = "Aldosterone, Eplerenone, Insulin receptor substrate-1, Insulin resistance, Metabolic syndrome, Oxidative stress, Type 2 diabetes mellitus",
author = "Hirofumi Hitomi and Hideyasu Kiyomoto and Akira Nishiyama and Taiga Hara and Kumiko Moriwaki and Kumiko Kaifu and Genei Ihara and Yoshiko Fujita and Toyomu Ugawa and Masakazu Kohno",
year = "2007",
month = "10",
doi = "10.1161/HYPERTENSIONAHA.107.093955",
language = "English",
volume = "50",
pages = "750--755",
journal = "Hypertension",
issn = "0194-911X",
publisher = "Lippincott Williams and Wilkins",
number = "4",

}

TY - JOUR

T1 - Aldosterone suppresses insulin signaling via the downregulation of insulin receptor substrate-1 in vascular smooth muscle cells

AU - Hitomi, Hirofumi

AU - Kiyomoto, Hideyasu

AU - Nishiyama, Akira

AU - Hara, Taiga

AU - Moriwaki, Kumiko

AU - Kaifu, Kumiko

AU - Ihara, Genei

AU - Fujita, Yoshiko

AU - Ugawa, Toyomu

AU - Kohno, Masakazu

PY - 2007/10

Y1 - 2007/10

N2 - Clinical reports indicate that patients with primary aldosteronism commonly have impaired glucose tolerance; however, the relationship between aldosterone and insulin signaling pathway has not been clarified. In this study, we examined the effects of aldosterone treatment on insulin receptor substrate-1 expression and insulin signaling pathway including Akt phosphorylation and glucose uptake in rat vascular smooth muscle cells. Insulin receptor substrate-1 protein expression and Akt phosphorylation were determined by Western blot analysis with anti-insulin receptor substrate-1 and phosphorylated-Akt antibodies, respectively. Glucose metabolism was evaluated using H-labeled 2-deoxy-d-glucose uptake. Aldosterone (1-100 nmol/L) dose-dependently decreased insulin receptor substrate-1 protein expression with a peak at 18 hours (n=4). Aldosterone-induced degradation of insulin receptor substrate-1 was markedly attenuated by treatment with the selective mineralocorticoid receptor antagonist eplerenone (10 μmol/L; n=4). Furthermore, degradation was blocked by the Src inhibitor PP1 (20 μmol/L; n=4). Treatment with antioxidants, N-acetylcysteine (10 mmol/L), or ebselen (40 μmol/L) also attenuated aldosterone-induced insulin receptor substrate-1 degradation (n=4). In addition, proteasome inhibitor MG132 (1 μmol/L) prevented insulin receptor substrate-1 degradation (n=4). Aldosterone treatment abolished insulin-induced Akt phosphorylation (100 nmol/L; 5 minutes; n=4). Furthermore, aldosterone pretreatment decreased insulin-stimulated (100 nmol/L; 60 minutes; n=4) glucose uptake by 50%, which was reversed by eplerenone (10 μmol/L; n=4). These data indicate that aldosterone decreases insulin receptor substrate-1 expression via Src and reactive oxygen species stimulation by proteasome-dependent degradation in vascular smooth muscle cells; thus, aldosterone may be involved in the pathogenesis of vascular insulin resistance via oxidative stress.

AB - Clinical reports indicate that patients with primary aldosteronism commonly have impaired glucose tolerance; however, the relationship between aldosterone and insulin signaling pathway has not been clarified. In this study, we examined the effects of aldosterone treatment on insulin receptor substrate-1 expression and insulin signaling pathway including Akt phosphorylation and glucose uptake in rat vascular smooth muscle cells. Insulin receptor substrate-1 protein expression and Akt phosphorylation were determined by Western blot analysis with anti-insulin receptor substrate-1 and phosphorylated-Akt antibodies, respectively. Glucose metabolism was evaluated using H-labeled 2-deoxy-d-glucose uptake. Aldosterone (1-100 nmol/L) dose-dependently decreased insulin receptor substrate-1 protein expression with a peak at 18 hours (n=4). Aldosterone-induced degradation of insulin receptor substrate-1 was markedly attenuated by treatment with the selective mineralocorticoid receptor antagonist eplerenone (10 μmol/L; n=4). Furthermore, degradation was blocked by the Src inhibitor PP1 (20 μmol/L; n=4). Treatment with antioxidants, N-acetylcysteine (10 mmol/L), or ebselen (40 μmol/L) also attenuated aldosterone-induced insulin receptor substrate-1 degradation (n=4). In addition, proteasome inhibitor MG132 (1 μmol/L) prevented insulin receptor substrate-1 degradation (n=4). Aldosterone treatment abolished insulin-induced Akt phosphorylation (100 nmol/L; 5 minutes; n=4). Furthermore, aldosterone pretreatment decreased insulin-stimulated (100 nmol/L; 60 minutes; n=4) glucose uptake by 50%, which was reversed by eplerenone (10 μmol/L; n=4). These data indicate that aldosterone decreases insulin receptor substrate-1 expression via Src and reactive oxygen species stimulation by proteasome-dependent degradation in vascular smooth muscle cells; thus, aldosterone may be involved in the pathogenesis of vascular insulin resistance via oxidative stress.

KW - Aldosterone

KW - Eplerenone

KW - Insulin receptor substrate-1

KW - Insulin resistance

KW - Metabolic syndrome

KW - Oxidative stress

KW - Type 2 diabetes mellitus

UR - http://www.scopus.com/inward/record.url?scp=34548850880&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34548850880&partnerID=8YFLogxK

U2 - 10.1161/HYPERTENSIONAHA.107.093955

DO - 10.1161/HYPERTENSIONAHA.107.093955

M3 - Article

C2 - 17646573

AN - SCOPUS:34548850880

VL - 50

SP - 750

EP - 755

JO - Hypertension

JF - Hypertension

SN - 0194-911X

IS - 4

ER -