Activation of Orexin 1 Receptors in the Paraventricular Nucleus Contributes to the Development of Deoxycorticosterone Acetate-Salt Hypertension Through Regulation of Vasopressin.
Activation of Orexin 1 Receptors in the Paraventricular Nucleus Contributes to the Development of Deoxycorticosterone Acetate-Salt Hypertension Through Regulation of Vasopressin.
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DOI：
10.3389/fphys.2021.641331
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发表时间：
2021
影响因子：
4
通讯作者：
Shan Z
中科院分区：
文献类型：
--
作者：
Bigalke JA;Gao H;Chen QH;Shan Z
盐敏感性是高血压发生的主要因素。已经观察到脑食欲素系统在许多高血压动物模型中起作用。然而，食欲素在盐敏感性高血压（SSH）的病理作用仍有待充分探讨。我们评估了食欲素过度活跃在醋酸脱氧皮质酮（DOCA）-盐大鼠模型的发病机制中的影响，特别是通过精氨酸加压素（AVP）的调节。成年雄性大鼠分为三组：载体对照组、DOCA-盐组和DOCA-盐+OX 1 R-shRNA组。DOCA-盐大鼠接受皮下植入21天释放的75 mg DOCA颗粒以及盐水饮用水（1% NaCl和0.2% KCl）。DOCA盐+OX 1 R-shRNA大鼠接受双侧室旁核（PVN）微量注射AAV 2-OX 1 R-shRNA以敲低该区域内的食欲素1受体（OX 1 R）功能。在2周后允许完全转基因表达，除了盐水饮用溶液之外还施用DOCA沉淀。载体对照接受假DOCA植入，但给予正常水。在3周DOCA-盐或假处理期间，使用尾袖体积描记法监测平均动脉压（MAP）和心率（HR）。3周后，收集大鼠脑进行PCR mRNA分析以及免疫染色。收集血浆样品并进行ELISA分析。与我们的假设一致，与对照组相比，DOCA-盐处理的大鼠PVN中OX 1 R表达升高。此外，在OX 1 R的慢性敲除后，DOCA盐处理正常诱导的高血压发展在DOCA盐+OX 1 R-shRNA组中显著减少。在AAV 2-OX 1 R-shRNA处理后，观察到PVN OX 1 R和AVP mRNA的同时减少与血压降低一致。类似地，与DOCA盐大鼠相比，DOCA盐+OX 1 R-shRNA组的血浆AVP浓度似乎降低。这些结果表明食欲素信号传导，特别是通过PVN中的OX 1 R，对于DOCA-盐模型中高血压的发作和维持至关重要。这种关系是介导的，至少部分地，通过食欲素激活AVP产生神经元，并随后释放AVP到外周。我们的研究结果概述了一个有前途的机制，通过与大脑食欲素系统的相互作用，SSH的发展。
Salt-sensitivity is a major factor in the development of hypertension. The brain orexin system has been observed to play a role in numerous hypertensive animal models. However, orexin’s role in the pathology of salt-sensitive hypertension (SSH) remains to be adequately explored. We assessed the impact of orexin hyperactivity in the pathogenesis of the deoxycorticosterone acetate (DOCA) – salt rat model, specifically through modulation of Arginine Vasopressin (AVP). Adult male rats were separated into three groups: vehicle control, DOCA-salt, and DOCA-salt+OX1R-shRNA. DOCA-salt rats received subcutaneous implantation of a 21-day release, 75 mg DOCA pellet in addition to saline drinking water (1% NaCl and 0.2% KCl). DOCA-salt+OX1R-shRNA rats received bilateral microinjection of AAV2-OX1R-shRNA into the paraventricular nucleus (PVN) to knockdown function of the Orexin 1-Receptor (OX1R) within that area. Following 2-week to allow full transgene expression, a DOCA pellet was administered in addition to saline drinking solution. Vehicle controls received sham DOCA implantation but were given normal water. During the 3-week DOCA-salt or sham treatment period, mean arterial pressure (MAP) and heart rate (HR) were monitored utilizing tail-cuff plethysmography. Following the 3-week period, rat brains were collected for either PCR mRNA analysis, as well as immunostaining. Plasma samples were collected and subjected to ELISA analysis. In line with our hypothesis, OX1R expression was elevated in the PVN of DOCA-salt treated rats when compared to controls. Furthermore, following chronic knockdown of OX1R, the hypertension development normally induced by DOCA-salt treatment was significantly diminished in the DOCA-salt+OX1R-shRNA group. A concurrent reduction in PVN OX1R and AVP mRNA was observed in concert with the reduced blood pressure following AAV2-OX1R-shRNA treatment. Similarly, plasma AVP concentrations appeared to be reduced in the DOCA-salt+OX1R-shRNA group when compared to DOCA-salt rats. These results indicate that orexin signaling, specifically through the OX1R in the PVN are critical for the onset and maintenance of hypertension in the DOCA-salt model. This relationship is mediated, at least in part, through orexin activation of AVP producing neurons, and the subsequent release of AVP into the periphery. Our results outline a promising mechanism underlying the development of SSH through interactions with the brain orexin system.
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影响因子：
--
作者：
Hahn JD;Swanson LW
通讯作者：
Swanson LW
DOI：
10.1161/hypertensionaha.114.03791
发表时间：
2014-11
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
--
作者：
Crosswhite P;Chen K;Sun Z
通讯作者：
Sun Z
DOI：
10.1111/apha.12963
发表时间：
2018-03
期刊：
Acta physiologica (Oxford, England)
影响因子：
--
作者：
Fan Y;Jiang E;Hahka T;Chen QH;Yan J;Shan Z
通讯作者：
Shan Z
影响因子：
8.3
作者：
BERECEK, KH;BARRON, KW;BRODY, MJ
通讯作者：
BRODY, MJ
DOI：
10.1152/ajpheart.00086.2011
发表时间：
2011-11-01
影响因子：
4.8
作者：
Kandlikar, Sachin S.;Fink, Gregory D.
通讯作者：
Fink, Gregory D.