alexa Angiotensin II-induced upregulation of AT(1) receptor expression: sequential activation of NF-kappaB and Elk-1 in neurons.


Journal of Clinical & Experimental Cardiology

Author(s): Mitra AK, Gao L, Zucker IH

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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 (AT(1)R) are important mediators in the pathophysiology of several diseases characterized by sympatho-excitation. In an effort to further understand the regulation of AT(1)R expression in neurons, we determined the role of sequential activation of the transcription factors nuclear factor-kappaB (NF-kappaB) and Ets-like protein 1 (Elk-1) in AT(1)R 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-kappaB that was observed at 30 min, peaked at 1 h, and was sustained up to 24 h. There was a concomitant decrease of IkappaB and increased IkappaK expression. We also observed an increase in AT(1)R expression which followed the temporal increase of NF-kappaB. The activation of NF-kappaB was blocked by using the inhibitors parthenolide or p65 small interfering RNA (siRNA) which both led to a decrease in AT(1)R expression. The expression of Elk-1 was upregulated over a time period following ANG II activation and was decreased following NF-kappaB 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-kappaB and Elk-1 in the upregulation of AT(1)R 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.
This article was published in Am J Physiol Cell Physiol and referenced in Journal of Clinical & Experimental Cardiology

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