title: 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.
  
  
  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.affiliation: Department of Pharmacology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Shamshad J
authors.initials: SJ
authors.lastname: Sherajee
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Fujita
authors.forename: Kazi
authors.initials: K
authors.lastname: Rafiq
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nakano
authors.forename: Hirohito
authors.initials: H
authors.lastname: Mori
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Masaki
authors.forename: Taiga
authors.initials: T
authors.lastname: Hara
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kohno
authors.forename: Akira
authors.initials: A
authors.lastname: Nishiyama
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Hitomi
mesh_terms: D000450:Aldosterone / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001794:Blood Pressure / Q000187:drug effects; D002478:Cells, Cultured; D002678:Chimera / Q000235:genetics; D000077545:Eplerenone; D005947:Glucose / Q000378:metabolism; D006984:Hypertrophy; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance; D008297:Male; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism*; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D007328:Insulin; D013148:Spironolactone; D000450:Aldosterone; D000077545:Eplerenone; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D005947:Glucose