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(Hypertension. 2007;50:750.)
© 2007 American Heart Association, Inc.

XVIIth Scientific Meeting of the Inter-American Society of Hypertension

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

From the Department of Cardiorenal and Cerebrovascular Medicine (H.H., H.K., T.H., K.M., K.K., G.I., Y.F., T.U., M.K.) and Department of Pharmacology (A.N.), Faculty of Medicine, Kagawa University, Kagawa, Japan.

Correspondence to Hirofumi Hitomi, Kagawa University, Department of Cardiorenal and Cerebrovascular Medicine, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan. E-mail hitomi{at}kms.ac.jp

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 ³H-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.

Key Words: aldosterone • oxidative stress • insulin receptor substrate-1 • insulin resistance • type 2 diabetes mellitus • metabolic syndrome • eplerenone

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