Bigalke Jeremy A, Gao Huanjia, Chen Qing-Hui, Shan Zhiying
Department of Kinesiology and Integrative Physiology, Michigan Technological University, Houghton, MI, United States.
Department of Psychology, Montana State University, Bozeman, MT, United States.
Front Physiol. 2021 Feb 3;12:641331. doi: 10.3389/fphys.2021.641331. eCollection 2021.
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.
盐敏感性是高血压发生发展的一个主要因素。在众多高血压动物模型中，已观察到脑食欲素系统发挥了作用。然而，食欲素在盐敏感性高血压（SSH）病理过程中的作用仍有待充分探索。我们评估了食欲素活性亢进在醋酸脱氧皮质酮（DOCA）-盐大鼠模型发病机制中的影响，具体是通过调节精氨酸加压素（AVP）来进行评估。成年雄性大鼠被分为三组：载体对照组、DOCA-盐组和DOCA-盐+OX1R-shRNA组。DOCA-盐组大鼠除饮用盐水（1% NaCl和0.2% KCl）外，还皮下植入了一个21天缓释、75 mg的DOCA微丸。DOCA-盐+OX1R-shRNA组大鼠双侧脑室旁核（PVN）微量注射AAV2-OX1R-shRNA，以敲低该区域食欲素1受体（OX1R）的功能。在2周后使转基因充分表达，然后除给予盐溶液外，再给予DOCA微丸。载体对照组接受假DOCA植入，但给予正常饮水。在3周的DOCA-盐处理或假手术治疗期间，利用尾套体积描记法监测平均动脉压（MAP）和心率（HR）。在3周后，收集大鼠大脑进行PCR mRNA分析以及免疫染色。收集血浆样本并进行ELISA分析。与我们的假设一致，与对照组相比，DOCA-盐处理大鼠PVN中的OX1R表达升高。此外，在DOCA-盐+OX1R-shRNA组中，OX1R慢性敲低后，DOCA-盐处理通常诱导的高血压发展显著减轻。在AAV2-OX1R-shRNA处理后，随着血压降低，同时观察到PVN中OX1R和AVP mRNA减少。同样，与DOCA-盐组大鼠相比，DOCA-盐+OX1R-shRNA组血浆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OX1R，对于DOCA-盐模型中高血压的发生和维持至关重要。这种关系至少部分是通过食欲素激活产生AVP的神经元，并随后将AVP释放到外周来介导的。我们的结果概述了通过与脑食欲素系统相互作用而形成SSH的一种有前景的机制。
