Aldosterone induces vascular insulin resistance by increasing insulin-like growth factor-1 receptor and hybrid receptor.

Abstract

OBJECTIVE:

We previously showed that aldosterone induces insulin resistance in rat vascular smooth muscle cells (VSMCs). Because insulin-like growth factor-1 receptor (IGF1R) affects insulin signaling, we hypothesized that aldosterone induces vascular insulin resistance and remodeling via upregulation of IGF1R and its hybrid insulin/insulin-like growth factor-1 receptor.

METHODS AND RESULTS:

Hybrid receptor expression was measured by immunoprecipitation. Hypertrophy of VSMCs was evaluated by (3)H-labeled leucine incorporation. Aldosterone (10 nmol/L) significantly increased protein and mRNA expression of IGF1R and hybrid receptor in VSMCs but did not affect insulin receptor expression. Mineralocorticoid receptor blockade with eplerenone inhibited aldosterone-induced increases in IGF1R and hybrid receptor. Aldosterone augmented insulin (100 nmol/L)-induced extracellular signal-regulated kinase 1/2 phosphorylation. Insulin-induced leucine incorporation and α-smooth muscle actin expression were also augmented by aldosterone in VSMCs. These aldosterone-induced changes were significantly attenuated by eplerenone or picropodophyllin, an IGF1R inhibitor. Chronic infusion of aldosterone (0.75 μg/hour) increased blood pressure and aggravated glucose metabolism in rats. Expression of hybrid receptor, azan-positive area, and oxidative stress in aorta was increased in aldosterone-infused rats. Spironolactone and tempol prevented these aldosterone-induced changes.

CONCLUSIONS:

Aldosterone induces vascular remodeling through IGF1R- and hybrid receptor-dependent vascular insulin resistance. Mineralocorticoid receptor blockade may attenuate angiopathy in hypertensive patients with hyperinsulinemia.

• Authors: Shamshad J Sherajee, Yoshiko Fujita, Kazi Rafiq, Daisuke Nakano, Hirohito Mori, Tsutomu Masaki, Taiga Hara, Masakazu Kohno, Akira Nishiyama, Hirofumi Hitomi
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 32 Issue 2 Pg. 257-63 (Feb 2012) ISSN: 1524-4636 [Electronic] United States
• PMID: 22173225 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Insulin
• Spironolactone
• Aldosterone
• Eplerenone
• Receptor, IGF Type 1
• Receptor, Insulin
• Glucose

Topics

• Aldosterone (pharmacology)
• Animals
• Aorta, Thoracic (drug effects, metabolism, pathology)
• Blood Pressure (drug effects)
• Cells, Cultured
• Chimera (genetics)
• Eplerenone
• Glucose (metabolism)
• Hypertrophy
• Insulin (pharmacology)
• Insulin Resistance
• Male
• Models, Animal
• Muscle, Smooth, Vascular (drug effects, metabolism, pathology)
• Oxidative Stress (drug effects)
• Rats
• Rats, Sprague-Dawley
• Receptor, IGF Type 1 (genetics, metabolism)
• Receptor, Insulin (genetics, metabolism)
• Spironolactone (analogs & derivatives, pharmacology)
• Up-Regulation (drug effects)