背景:原发性高血压的发展与多种机制有关。脑干神经元对动脉压的稳态调节至关重要,因为它们控制压力反射和交感神经活动。ISIAH(遗传性应激诱导的动脉高血压)大鼠以神经内分泌下丘脑-垂体-肾上腺和交感神经肾上腺轴的主要激活再现了人类应激敏感性高血压疾病。对高血压ISIAH和正常血压对照WAG(WistarAlbinoGlaxo)大鼠的脑干进行RNA-Seq分析,以鉴定差异表达基因(DEGs)和导致高血压的主要中心机制(生物过程和代谢途径)ISIAH大鼠的状态。
结果:研究显示224个DEG。他们在数据库中的注释显示,其中22个与高血压和血压(BP)调节有关,61个DEGs与中枢神经系统疾病有关。根据DEG的功能注释,荷尔蒙代谢过程的关键作用,特别是,提出了增强ISIAH大鼠脑干醛固酮的生物合成。鉴定了与多个基因本体论(GO)术语相关的多个DEGs,这些术语基本上与BP的调节相关。大量的DEGs与GO术语相关,这些术语与对不同刺激的反应相关,包括对有机(激素)物质的反应,外部刺激,和压力。检测到几个对菌株间差异做出最大贡献的DEGs,包括Ephx2,该基因较早被定义为不同组织/器官转录谱研究中的主要候选基因(下丘脑,ISIAH大鼠的肾上腺和肾脏)。
结论:研究结果表明,ISIAH和WAG脑干功能的应变间差异可能是导致病理发展的过程失衡的结果,发挥补偿作用。这项研究中获得的数据有助于更好地了解ISIAH大鼠脑干过程复杂性的遗传机制,这是压力敏感型高血压的模型。
BACKGROUND: The development of essential hypertension is associated with a wide range of mechanisms. The brain stem neurons are essential for the homeostatic regulation of arterial pressure as they control baroreflex and sympathetic nerve activity. The ISIAH (Inherited Stress Induced Arterial Hypertension) rats reproduce the human stress-sensitive hypertensive disease with predominant activation of the neuroendocrine hypothalamic-pituitary-adrenal and sympathetic adrenal axes. RNA-Seq analysis of the brain stems from the hypertensive ISIAH and normotensive control WAG (Wistar Albino Glaxo) rats was performed to identify the differentially expressed genes (DEGs) and the main central mechanisms (biological processes and metabolic pathways) contributing to the hypertensive state in the ISIAH rats.
RESULTS: The study revealed 224 DEGs. Their annotation in databases showed that 22 of them were associated with hypertension and blood pressure (BP) regulation, and 61 DEGs were associated with central nervous system diseases. In accordance with the functional annotation of DEGs, the key role of hormonal metabolic processes and, in particular, the enhanced biosynthesis of aldosterone in the brain stem of ISIAH rats was proposed. Multiple DEGs associated with several Gene Ontology (GO) terms essentially related to modulation of BP were identified. Abundant groups of DEGs were related to GO terms associated with responses to different stimuli including response to organic (hormonal) substance, to external stimulus, and to stress. Several DEGs making the most contribution to the inter-strain differences were detected including the Ephx2, which was earlier defined as a major candidate gene in the studies of transcriptional profiles in different tissues/organs (hypothalamus, adrenal gland and kidney) of ISIAH rats.
CONCLUSIONS: The results of the study showed that inter-strain differences in ISIAH and WAG brain stem functioning might be a result of the imbalance in processes leading to the pathology development and those, exerting the compensatory effects. The data obtained in this study are useful for a better understanding of the genetic mechanisms underlying the complexity of the brain stem processes in ISIAH rats, which are a model of stress-sensitive form of hypertension.