Department of Physiology and Functional Genomics, University of Florida, Gainesville, FL 32610, USA.
Hypertension. 2013 Mar;61(3):622-7. doi: 10.1161/HYPERTENSIONAHA.111.199836. Epub 2013 Jan 14.
The importance of the (pro)renin receptor (PRR) in the function of the central nervous system is increasingly evident because PRR seems to play a role in neuronal control of cardiovascular function. PRR expression is elevated in the nucleus of the solitary tract (NTS) of spontaneously hypertensive rats (SHR). In this study, we tested the hypothesis that altered activity of PRR in the NTS is linked to hypertension. Eight weeks of chronic knockdown of the NTS PRR, using recombinant adeno-associated virus type 2 (AAV2)-PRR-small hairpain RNA (shRNA)-mediated gene transduction, caused a significant increase in mean arterial pressure (MAP) in the SHR (shRNA, 173±5; Control, 151±6 mm Hg) but not in Wistar Kyoto rats (shRNA, 108±7; Control, 106±6 mm Hg). The MAP elevation in the SHR was associated with decreased inflammatory markers tumor necrosis factor-α, interleukin-6, C-C motif ligand 5, and their transcription factor, nuclear factor-κB. Consistent with the pressor effects of the PRR knockdown, acute bilateral NTS injection of human renin (2 pmol/side) decreased MAP and heart rate (HR) in SHR (ΔMAP, -38±4 mm Hg; Δheart rate, -40±10 bpm), with negligible responses in Wistar Kyoto rats (ΔMAP, -4±3 mm Hg; Δheart rate, -12±7 bpm). These effects in SHR were attenuated (80%) by prorenin handle region peptide but were not affected by angiotensin II type 1 or angiotensin II type 2 receptor blockers. Finally, PRR activation in SHR neuronal cultures by prorenin activated nuclear factor-κB and increased mRNA levels of interleukin-1β (250-fold), tumor necrosis factor-α (32-fold), interleukin-6 (35-fold), C-C motif ligand 5 (12-fold), and interleukin-10 (7-fold) in a nuclear factor-κB-dependent but angiotensin II type 1 receptor-independent manner. Therefore, NTS PRR mediates antihypertensive effects via an angiotensin II-independent mechanism in SHR, which involves stimulation of the nuclear factor-κB-cytokine signaling pathway.
（前）肾素受体（PRR）在中枢神经系统功能中的重要性日益明显，因为 PRR 似乎在神经元对心血管功能的控制中发挥作用。PRR 在自发性高血压大鼠（SHR）的孤束核（NTS）中的表达升高。在这项研究中，我们检验了这样一个假设，即 NTS 中 PRR 活性的改变与高血压有关。使用重组腺相关病毒 2（AAV2）-PRR-短发夹 RNA（shRNA）介导的基因转导，对 NTS 的 PRR 进行 8 周的慢性敲低，导致 SHR 的平均动脉压（MAP）显著升高（shRNA，173±5；Control，151±6mmHg），但 Wistar Kyoto 大鼠的 MAP 没有升高（shRNA，108±7；Control，106±6mmHg）。SHR 中的 MAP 升高与炎症标志物肿瘤坏死因子-α、白细胞介素-6、C-C 基序配体 5 及其转录因子核因子-κB 的减少有关。与 PRR 敲低的加压作用一致，急性双侧 NTS 注射人肾素（2pmol/侧）降低了 SHR 的 MAP 和心率（HR）（ΔMAP，-38±4mmHg；Δ心率，-40±10bpm），而 Wistar Kyoto 大鼠的反应可忽略不计（ΔMAP，-4±3mmHg；Δ心率，-12±7bpm）。这些在 SHR 中的作用被前肾素处理区肽（80%）减弱，但不受血管紧张素 II 型 1 或血管紧张素 II 型 2 受体阻滞剂的影响。最后，PRR 在 SHR 神经元培养物中的激活通过前肾素激活核因子-κB，并以核因子-κB 依赖性但血管紧张素 II 型 1 受体非依赖性的方式增加白细胞介素-1β（250 倍）、肿瘤坏死因子-α（32 倍）、白细胞介素-6（35 倍）、C-C 基序配体 5（12 倍）和白细胞介素-10（7 倍）的 mRNA 水平。因此，NTS PRR 通过 SHR 中的一种血管紧张素 II 独立机制介导降压作用，该机制涉及核因子-κB-细胞因子信号通路的刺激。
