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

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112 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 1 2007

Keywords

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

ASJC Scopus subject areas

  • Internal Medicine

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    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, 50(4), 750-755. https://doi.org/10.1161/HYPERTENSIONAHA.107.093955