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Vol. 24, No. 4, 2004
Issue release date: July–August 2004
Section title: Original Report: Laboratory Investigation
Am J Nephrol 2004;24:415–421
(DOI:10.1159/000080086)

Angiotensin II Induces Hypoxia-Inducible Factor-1α in PC 12 Cells through a Posttranscriptional Mechanism: Role of AT2 Receptors

Wolf G. · Schroeder R. · Stahl R.A.K.
Department of Medicine, Division of Nephrology and Osteology, University of Hamburg, Hamburg, Germany

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Article / Publication Details

First-Page Preview
Abstract of Original Report: Laboratory Investigation

Received: 2/17/2004
Accepted: 7/1/2004
Published online: 9/17/2004

Number of Print Pages: 7
Number of Figures: 5
Number of Tables: 0

ISSN: 0250-8095 (Print)
eISSN: 1421-9670 (Online)

For additional information: http://www.karger.com/AJN

Abstract

Background: Angiotensin II (ANG II) inhibits proliferation and induces differentiation in PC 12 cells via AT2 receptor activation. Using differential display analysis, we previously isolated SM-20/PHD3 as a key factor, which is downregulated by ANG II treatment. Subsequently, it turned out that SM-20/PHD3 is a rat homologue of PHD3, a key prolyl hydroxylase involved in the initial steps fostering the degradation of hypoxia-inducible factor (HIF). The present study was undertaken to investigate whether the ANG-II-mediated suppression of SM-20/PHD3/PHD3 may be associated with an increase in HIF-1α. Methods: HIF-1α protein expression was assessed by Western blots. mRNA levels for HIF-1α were measured by real-time PCR and for SM-20/PHD3 by Northern blots. Binding of HIF-1α to consensus oligonucleotides in vitro was determined with gel shift analysis. SM-20/PHD3 was transiently overexpressed in PC 12 cells using an inducible expression system. Results: ANG II stimulated HIF-1α protein expression. This effect was already detected after 30 min and peaked at 6 h, but was not detectable anymore after 24– 48 h of stimulation. PD 123177, but not losartan, antagonized this effect, indicating transduction through AT2 receptors. Real-time PCR failed to show a significant increase in HIF-1α transcripts after ANG II challenge at any time point. Gel shift analysis revealed that ANG-II-induced nuclear HIF-1α protein binds to consensus sites. A reduction in SM-20/PHD3 mRNA expression paralleled the increase in HIF-1α. Overexpression of SM-20/PHD3 transiently resulted in a decrease in HIF-1α protein concentrations under basal conditions as well as after stimulation with ANG II. Conclusion: ANG II stimulates HIF-1α expression by a posttranscriptional mechanism via AT2 receptors. This increase is likely caused by a downregulation of SM-20/PHD3. The ANG-II-mediated increase in HIF-1α expression could be potentially involved in physiological as well as pathophysiological processes such as differentiation, growth inhibition, and remodeling.


  

Author Contacts

Gunter Wolf, MD
University of Hamburg, University Hospital Eppendorf, Department of Medicine, Division of Nephrology and Osteology, Pavilion N26, Martinistrasse 52,
DE–20246 Hamburg (Germany)
Tel. +49 40 42803 5011, Fax +49 40 42803 5186, E-Mail wolf@uke.uni-hamburg.de

  

Article Information

Received: February 17, 2004
Accepted: July 1, 2004
Published online: August 11, 2004
Number of Print Pages : 7
Number of Figures : 5, Number of Tables : 0, Number of References : 26

  

Publication Details

American Journal of Nephrology

Vol. 24, No. 4, Year 2004 (Cover Date: July-August 2004)

Journal Editor: Bakris, G. (Chicago, Ill.)
ISSN: 0250–8095 (print), 1421–9670 (Online)

For additional information: http://www.karger.com/ajn


Article / Publication Details

First-Page Preview
Abstract of Original Report: Laboratory Investigation

Received: 2/17/2004
Accepted: 7/1/2004
Published online: 9/17/2004

Number of Print Pages: 7
Number of Figures: 5
Number of Tables: 0

ISSN: 0250-8095 (Print)
eISSN: 1421-9670 (Online)

For additional information: http://www.karger.com/AJN


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