Aldosterone potentiates angiotensin II-induced signaling in vascular smooth muscle cells

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(-7) mol/L) and Ald (10(-7) 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 II + Ald 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(-6) 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.