| Angiotensin II signaling via type 2 receptors in a human model of vascular hyporeactivity: implications for hypertension. | |
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MedLine Citation:
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PMID: 19797979 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Lorenzo A Cal?; Silvia Schiavo; Paul A Davis; Elisa Pagnin; Paolo Mormino; Angela D'Angelo; Achille C Pessina |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Journal of hypertension Volume: 28 ISSN: 1473-5598 ISO Abbreviation: J. Hypertens. Publication Date: 2010 Jan |
Date Detail:
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Created Date: 2009-12-17 Completed Date: 2010-03-09 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8306882 Medline TA: J Hypertens Country: England |
Other Details:
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Languages: eng Pagination: 111-8 Citation Subset: IM |
Affiliation:
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Department of Clinical and Experimental Medicine, Clinica Medica 4, University of Padova, Padova, Italy. renzcalo@unipd.it |
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| MeSH Terms | |
Descriptor/Qualifier:
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Adult Angiotensin II / metabolism* Angiotensin II Type 1 Receptor Blockers / pharmacology Bartter Syndrome / metabolism*, pathology Cells, Cultured Drug Combinations Dual Specificity Phosphatase 1 / metabolism Female Fibroblasts / metabolism, pathology Gitelman Syndrome / metabolism*, physiopathology Humans Hypertension / metabolism*, pathology Imidazoles / pharmacology Losartan / pharmacology MAP Kinase Signaling System / physiology Male Middle Aged Mitogen-Activated Protein Kinase 3 / metabolism Phosphorylation Pyridines / pharmacology Receptor, Angiotensin, Type 1 / metabolism Receptor, Angiotensin, Type 2 / antagonists & inhibitors, metabolism* |
| Chemical | |
Reg. No./Substance:
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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 2.7.11.24/Mitogen-Activated Protein Kinase 3; EC 3.1.3.48/DUSP1 protein, human; EC 3.1.3.48/Dual Specificity Phosphatase 1 |
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