Aldosterone Suppresses Insulin Signaling Via the Downregulation of Insulin Receptor Substrate-1 in Vascular Smooth Muscle Cells

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 50; no. 4; pp. 750 - 755
• Main Authors: Hitomi, Hirofumi, Kiyomoto, Hideyasu, Nishiyama, Akira, Hara, Taiga, Moriwaki, Kumiko, Kaifu, Kumiko, Ihara, Genei, Fujita, Yoshiko, Ugawa, Toyomu, Kohno, Masakazu
• Format: Journal Article Conference Proceeding
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01-10-2007; Hagerstown, MD Lippincott
• Subjects: Aldosterone - physiology; Angiotensin II - pharmacology; Animals; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Blood vessels and receptors; Cardiology. Vascular system; Cells, Cultured; Down-Regulation; Fundamental and applied biological sciences. Psychology; Insulin - physiology; Insulin Receptor Substrate Proteins; Insulin Resistance - physiology; Medical sciences; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - metabolism; Oncogene Protein v-akt - metabolism; Phosphoproteins - genetics; Phosphoproteins - metabolism; Phosphorylation; Proteasome Endopeptidase Complex - physiology; Rats; Reactive Oxygen Species - metabolism; Signal Transduction - physiology; src-Family Kinases - physiology; Vertebrates: cardiovascular system; Endocrinopathy; Type 2 diabetes; Prostaglandin-endoperoxide synthase; Oxidative stress; Rat; Mineralocorticoid; Pathogenesis; Smooth muscle; Glucose; Aldosterone; Selenium Organic compounds; Vascular resistance; type 2 diabetes mellitus; Impaired glucose tolerance; insulin resistance; Human; insulin receptor substrate-1; Thiol; Enzyme; Steroid hormone; Rodentia; Enzyme inhibitor; Metabolic diseases; Ebselen; Antioxidant; Metabolism; Insulin; Uptake; Non steroidal antiinflammatory agent; metabolic syndrome; Aldosterone antagonist; Vertebrata; Mammalia; Treatment; Eplerenone; Animal; Adrenal hormone; Antihypertensive agent; Oxidoreductases; Hormonal receptor
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.107.093955

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.