Aldosterone Potentiates Angiotensin II–Induced Signaling in Vascular Smooth Muscle Cells

Abstract

Background-In a double-transgenic human renin and human angiotensinogen rat model, we found that mineralocorticoid receptor (MR) blockade ameliorated angiotensin II (Ang II)-induced renal and cardiac damage. How Ang II and aldosterone (Ald) might interact is ill defined. Methods and Results-We investigated the effects of Ang II (10 Ϫ7 mol/L) and Ald (10 Ϫ7 mol/L) on extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) signaling in vascular smooth muscle cells (VSMCs) with Western blotting and confocal microscopy. Ang II induced ERK 1/2 and JNK phosphorylation by 2 minutes. Ald achieved the same at 10 minutes. Ang IIϩAld had a potentiating effect by 2 minutes. Two oxygen radical scavengers and the epidermal growth factor receptor (EGFR) antagonist AG1478 reduced Ang II-, Ald-, and combination-induced ERK1/2 phosphorylation. Preincubating the cells with the MR blocker spironolactone (10 Ϫ6 mol/L) abolished Ang II-induced ROS generation, EGFR transactivation, and ERK1/2 phosphorylation. Conclusions-Ald potentiates Ang II-induced ERK-1/2 and JNK phosphorylation. Oxygen radicals, the MR, and the EGFR play a role in early signaling induced by Ang II and Ald in VSMCs. These in vitro data may help explain the effects of MR blockade on Ang II-induced end-organ damage in vivo.

Renin-Angiotensin-Aldosterone System and Progression of Renal Disease

“…In various animal models of renal diseases, aldosterone is involved in endothelial dysfunction, inflammation, proteinuria, and fibrosis (48). Aldosterone increases the effect of AngII, induces the generation of reactive oxygen species, and leads to an acceleration of the AngII-induced activation of mitogenactivated protein kinases (49). These findings indicate that blockade of mineralocorticoid receptors presumably is beneficial even in situations with high AngII, because common signal transduction pathways between the two systems are interrupted.…”

Effects of Aldosterone on the Vasculature

“…These results suggest that aldosterone exerts a mitogenic effect synergistic with Ang II and that blockade of both MR and Ang II may provide enhanced protection from vascular remodeling, as already reported by Iglarz et al 56 Ang II and aldosterone stimulate MAP kinase and ROS signaling. 47,55 Jaffe and Mendelsohn 57 showed that Ang II directly activates MRs in human coronary and aortic VSMCs (Figure 2). The presence of 11-␤-hydroxysteroiddehydrogenase-2, necessary for mineralocorticoid action, was also demonstrated.…”

ATM deficiency induces oxidative stress and endoplasmic reticulum stress in astrocytes

“…Recently, it has been shown that the MAPK/ERK stress pathway is redox sensitive. [39][40][41] To determine whether the increase in ERK1/2 phosphorylation and activation is a consequence of oxidative stress, we treated Atm À/À astrocytes with antioxidant N-acetylcyste (NAC). The activation of ERK1/2 in these astrocytes was suppressed by treatment with NAC (38% reduction for ERK1 and 36% reduction for ERK2, Figure 3d).…”