title: 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.
  
  
  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.
authors.affiliation: Medical Faculty of the Charité, Franz Volhard Clinic, HELIOS Klinikum-Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany.
authors.forename: Istvan
authors.initials: I
authors.lastname: Mazak
authors.forename: Anette
authors.initials: A
authors.lastname: Fiebeler
authors.forename: Dominik N
authors.initials: DN
authors.lastname: Muller
authors.forename: Joon-Keun
authors.initials: JK
authors.lastname: Park
authors.forename: Erdenechimeg
authors.initials: E
authors.lastname: Shagdarsuren
authors.forename: Carsten
authors.initials: C
authors.lastname: Lindschau
authors.forename: Ralf
authors.initials: R
authors.lastname: Dechend
authors.forename: Christiane
authors.initials: C
authors.lastname: Viedt
authors.forename: Bernhard
authors.initials: B
authors.lastname: Pilz
authors.forename: Hermann
authors.initials: H
authors.lastname: Haller
authors.forename: Friedrich C
authors.initials: FC
authors.lastname: Luft
mesh_terms: D000450:Aldosterone / Q000502:physiology*; D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D030801:Animals, Genetically Modified; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013148:Spironolactone / Q000494:pharmacology
chemical_list: D000451:Mineralocorticoid Receptor Antagonists; D017382:Reactive Oxygen Species; D000804:Angiotensin II; D013148:Spironolactone; D000450:Aldosterone; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases