Document Detail

Angiotensin II signaling via type 2 receptors in a human model of vascular hyporeactivity: implications for hypertension.
MedLine Citation:
PMID:  19797979     Owner:  NLM     Status:  MEDLINE    
OBJECTIVE: Angiotensin II (Ang II) signaling via type 1 receptor (AT1R) has been extensively characterized, whereas Ang II signaling via type 2 receptors (AT2R), although counteracts actions mediated by AT1R, is still not completely understood. Bartter's/Gitelman's patients (BS/GS) have intrinsically blunted AT1R signaling, making them a good model to examine Ang II signaling via AT2R with particular emphasis on mitogen-activated protein kinase phosphatase 1 (MKP-1) that interacts with the Ang II-stimulated ERK pathway of cell signaling. METHODS: BS/GS and healthy controls fibroblasts AT1R and AT2R level and the time course of Ang II's effect on MKP-1 levels and ERK1/2 phosphorylation over 1-h time course were assessed by western blot. The time course of Ang II's effect on MKP-1 levels and ERK1/2 phosphorylation alone or in the presence of either PD123319, an AT2R blocker, or Losartan, an AT1R blocker, or in combination was characterized. RESULTS: AT1R and AT2R levels did not differ between BS/GS and healthy controls. Ang II induced ERK1/2 phosphorylation in BS/GS fibroblasts, but peak ERK1/2 phosphorylation declined more rapidly than that in control and BS/GS fibroblasts also exhibited increased MKP-1 levels at 30-min incubation. PD123319, an AT2R blocker in BS/GS fibroblasts, abolished the increased MKP-1 and ERK1/2 phosphorylation time course became same as that for control. Losartan, an AT1R blocker, alone altered the time course of control fibroblast MKP-1 to mimic the increase seen in BS/GS fibroblasts, whereas ERK1/2 declined concomitantly. Treatment with Losartan and PD123319 in controls reduced MKP-1 and elevated ERK1/2 phosphorylation to the level observed in BS/GS patients treated with PD123319. CONCLUSION: ERK1/2 phosphorylation time course found in BS/GS fibroblasts tracked changes in MKP-1 levels and incubation with an AT2R blocker, PD123319, abrogated those responses. Losartan, an AT1R blocker, reproduced these changes in healthy controls, whereas the presence of both AT1R and AT2R inhibitors in controls abolished these changes. These data strongly suggest that MKP-1 is a major effector in altering ERK1/2 phosphorylation status. Moreover, the results provide insight into the blunted responses in BS/GS reported for Ang II short-term and long-term effects, the mechanisms responsible, and thereby yield additional support for the role of AT2R signaling in the proposed effects of Ang II AT1R blockers beyond AT1R blockade.
Lorenzo A Cal?; Silvia Schiavo; Paul A Davis; Elisa Pagnin; Paolo Mormino; Angela D'Angelo; Achille C Pessina
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of hypertension     Volume:  28     ISSN:  1473-5598     ISO Abbreviation:  J. Hypertens.     Publication Date:  2010 Jan 
Date Detail:
Created Date:  2009-12-17     Completed Date:  2010-03-09     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8306882     Medline TA:  J Hypertens     Country:  England    
Other Details:
Languages:  eng     Pagination:  111-8     Citation Subset:  IM    
Department of Clinical and Experimental Medicine, Clinica Medica 4, University of Padova, Padova, Italy.
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MeSH Terms
Angiotensin II / metabolism*
Angiotensin II Type 1 Receptor Blockers / pharmacology
Bartter Syndrome / metabolism*,  pathology
Cells, Cultured
Drug Combinations
Dual Specificity Phosphatase 1 / metabolism
Fibroblasts / metabolism,  pathology
Gitelman Syndrome / metabolism*,  physiopathology
Hypertension / metabolism*,  pathology
Imidazoles / pharmacology
Losartan / pharmacology
MAP Kinase Signaling System / physiology
Middle Aged
Mitogen-Activated Protein Kinase 3 / metabolism
Pyridines / pharmacology
Receptor, Angiotensin, Type 1 / metabolism
Receptor, Angiotensin, Type 2 / antagonists & inhibitors,  metabolism*
Reg. No./Substance:
0/Angiotensin II Type 1 Receptor Blockers; 0/Drug Combinations; 0/Imidazoles; 0/Pyridines; 0/Receptor, Angiotensin, Type 1; 0/Receptor, Angiotensin, Type 2; 11128-99-7/Angiotensin II; 114798-26-4/Losartan; 130663-39-7/PD 123319; EC Protein Kinase 3; EC protein, human; EC Specificity Phosphatase 1

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