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首页> 外文期刊>American Journal of Physiology >Mitra, A.K., Gao, L., Zucker, I.H.Angiotensin II-induced upregulation of AT 1 receptor expression: Sequential activation of NF-κB and Elk-1 in neurons
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Mitra, A.K., Gao, L., Zucker, I.H.Angiotensin II-induced upregulation of AT 1 receptor expression: Sequential activation of NF-κB and Elk-1 in neurons

机译：Mitra，A.K.，Gao，L.，Zucker，I.H.血管紧张素II诱导的AT 1受体表达上调：神经元中NF-κB和Elk-1的顺序激活

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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 1R) are important mediators in the pathophysiology of several diseases characterized by sympatho-excitation. In an effort to further understand the regulation of AT 1R 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 AT 1R 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 AT 1R 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 AT 1R 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.
机译：已经清楚地确定，增加的循环血管紧张素II（ANG II）与同时发生的脑和周围ANG II 1型受体（AT 1R）的上调在以交感神经为特征的几种疾病的病理生理中是重要的介质。为了进一步了解神经元中AT 1R表达的调控，我们确定了转录因子核因子-κB（NF-κB）和Ets样蛋白1（Elk-1）的顺序激活在AT 1R上调中的作用。我们使用CATH.a神经元作为我们的神经元细胞模型。在预设的时间过程中，用ANG II（100 nM）处理细胞。 ANG II激活后，NF-κB的p65亚基随时间增加，在30分钟时观察到，在1小时达到峰值，并持续24小时。 IκB减少同时IκK表达增加。我们还观察到AT 1R表达增加，其随NF-κB的时间增加而增加。 NF-κB的激活被抑制剂单苯四酚或p65小干扰RNA（siRNA）阻断，两者均导致AT 1R表达降低。 Elk-1的表达在ANG II激活后的一段时间内上调，并在NF-κB抑制后降低。使用电泳迁移率变动分析评估了p65-DNA的结合，结果表明存在随时间变化的结合增加，该结合被单性酚预处理或siRNA介导的p65基因沉默所抑制。因此，我们的结果表明，转录因子NF-κB和Elk-1在CATH.a细胞神经元模型中AT 1R的上调中起联合作用。这些数据暗示一种正反馈机制，该机制可能会影响对ANG II的神经放电敏感性。

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