GLP1R 通过颈动脉体抑制来减轻高血糖引起的交感神经反应。

BACKGROUND: Aberrant sympathetic nerve activity exacerbates cardiovascular risk in hypertension and diabetes, which are common comorbidities, yet clinically sympathetic nerve activity remains poorly controlled. The hypertensive diabetic state is associated with increased reflex sensitivity and tonic drive from the peripheral chemoreceptors, the cause of which is unknown. We have previously shown hypertension to be critically dependent on the carotid body (CB) input in spontaneously hypertensive rat, a model that also exhibits a number of diabetic traits. CB overstimulation by insulin and leptin has been similarly implicated in the development of increased sympathetic nerve activity in metabolic syndrome and obesity. Thus, we hypothesized that in hypertensive diabetic state (spontaneously hypertensive rat), the CB is sensitized by altered metabolic signaling causing excessive sympathetic activity levels and dysfunctional reflex regulation. METHODS: Using a hypothesis-free RNA-seq approach, we investigated potential molecular targets implicated in energy metabolism mediating CB sensitization and its regulation of sympathetic outflow in experimental hypertension. Identified targets were characterized using molecular and functional techniques assessing peripheral chemoreflex sensitivity in situ and in vivo. RESULTS: We discovered GLP1R (glucagon-like peptide-1 receptor) expression in the CBs of rat and human and showed that its decreased expression is linked to sympathetic hyperactivity in rats with cardiometabolic disease. We demonstrate GLP1R to be localized to CB chemosensory cells, while targeted administration of GLP1R agonist to the CB lowered its basal discharge and attenuated chemoreflex-evoked blood pressure and sympathetic responses. Importantly, hyperglycemia-induced peripheral chemoreflex sensitization and associated basal sympathetic overactivity were abolished by GLP1R activation in the CB suggesting a role in a homeostatic response to high blood glucose. CONCLUSIONS: We show that GLP1 (glucagon-like peptide-1) modulates the peripheral chemoreflex acting on the CB, supporting this organ as a multimodal receptor. Our findings pinpoint CBs as potential targets for ameliorating excessive sympathetic activity using GLP1R agonists in the hypertensive-diabetic condition.

背景：异常的交感神经活动会加剧高血压和糖尿病患者的心血管风险，这两种疾病通常同时存在，但目前临床上对交感神经活动的控制仍不理想。高血压合并糖尿病状态与外周化学感受器的反射敏感性和紧张性驱动增加有关，但原因尚不清楚。我们之前的研究表明，在自发性高血压大鼠中，颈动脉体（CB）的输入对高血压起着至关重要的作用，而该模型还表现出许多糖尿病特征。胰岛素和瘦素对 CB 的过度刺激同样与代谢综合征和肥胖症中交感神经活性增加有关。因此，我们假设在高血压合并糖尿病状态（自发性高血压大鼠）中，改变的代谢信号会使 CB 敏感化，导致过度的交感神经活动水平和反射调节功能障碍。

方法：我们采用无假设的 RNA-seq 方法，研究了能量代谢中潜在的分子靶点，这些靶点可能介导 CB 敏化，并调节实验性高血压中的交感神经输出。通过原位和体内评估外周化学反射敏感性的分子和功能技术，对鉴定出的靶点进行了特征描述。

结果：我们发现 GLP1R（胰高血糖素样肽-1 受体）在大鼠和人类的 CB 中表达，并表明其表达降低与患有心脏代谢疾病的大鼠的交感神经过度活跃有关。我们证明 GLP1R 定位于 CB 化学感受细胞，而 GLP1R 激动剂靶向给药到 CB 会降低其基础放电，并减弱化学感受器诱发的血压和交感神经反应。重要的是，CB 中的 GLP1R 激活消除了高血糖诱导的外周化学感受器敏化和相关的基础交感神经过度活跃，提示其在对高血糖的稳态反应中起作用。

结论：我们表明，GLP1（胰高血糖素样肽-1）调节作用于 CB 的外周化学感受器反射，支持该器官作为一种多模态受体。我们的研究结果指出，CB 可能是在高血压合并糖尿病状态下，使用 GLP1R 激动剂改善过度交感神经活动的潜在靶点。