Angiotensin II-induced upregulation of AT1 receptor expression: Sequential activation of NF-κB and Elk-1 in neurons

Amit K. Mitra, Lie Gao, Irving H. Zucker

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Abstract

It has been clearly established that increased circulating angiotensin II (ANG II) with concurrent upregulation of brain and peripheral ANG II type 1 receptors (AT1R) are important mediators in the pathophysiology of several diseases characterized by sympatho-excitation. In an effort to further understand the regulation of AT1R expression in neurons, we determined the role of sequential activation of the transcription factors nuclear factor-κB (NF-κB) and Ets-like protein 1 (Elk-1) in AT 1R upregulation. We used CATH.a neurons as our neuronal cell model. Cells were treated with ANG II (100 nM) over a preset time course. Following ANG II activation, there was a temporal increase in the p65 subunit of NF-κB that was observed at 30 min, peaked at 1 h, and was sustained up to 24 h. There was a concomitant decrease of IκB and increased IκK expression. We also observed an increase in AT1R expression which followed the temporal increase of NF-κB. The activation of NF-κB was blocked by using the inhibitors parthenolide or p65 small interfering RNA (siRNA) which both led to a decrease in AT1R expression. The expression of Elk-1 was upregulated over a time period following ANG II activation and was decreased following NF-κB inhibition. p65-DNA binding was assessed using electrophoretic mobility shift assay, and it was shown that there was a time-dependent increased binding that was inhibited by means of parthenolide pretreatment or siRNA-mediated p65 gene silencing. Therefore, our results suggest a combined role for the transcription factors NF-κB and Elk-1 in the upregulation of AT1R in the CATH.a cell neuronal model. These data imply a positive feedback mechanism that may impact neuronal discharge sensitivity in response to ANG II.

Original languageEnglish (US)
Pages (from-to)C561-C569
JournalAmerican Journal of Physiology - Cell Physiology
Volume299
Issue number3
DOIs
StatePublished - Sep 1 2010

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Keywords

  • Angiotensin II type 1 receptor
  • CATH.a
  • Cell culture
  • G protein-coupled receptors
  • Small interfering RNA

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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