Aldosterone potentiates Angiotensin II-induced ERK-1/2 and JNK phosphorylation in vascular smooth muscle cells, an effect abolished by MR blockade with spironolactone.
Aldosterone potentiates Angiotensin II-induced signaling in vascular smooth muscle cells via oxygen radicals, MR, and EGFR, helping explain the in vivo benefits of MR blockade.
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.
Mazák et al. (Tue,) conducted a other in Angiotensin II-induced renal and cardiac damage. Angiotensin II and Aldosterone vs. Angiotensin II alone, Aldosterone alone, or MR blocker spironolactone was evaluated on extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) signaling. Aldosterone potentiates Angiotensin II-induced ERK-1/2 and JNK phosphorylation in vascular smooth muscle cells, an effect abolished by MR blockade with spironolactone.