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Early Life Stress & Chronic Control of Blood Pressure

早期生活压力

基本信息

批准号：
8896033
负责人：
Analia Loria
金额：
$ 24.9万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-23 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8896033
关键词：
Acute Adipose tissue Adrenergic Agents Adult Aldosterone Angiotensin II Attenuated Behavioral Biochemical Biological Blood Pressure Blood Vessels Cardiovascular Diseases Cardiovascular system Caring Child Childhood Chronic Corticosterone Data Development Diabetes Mellitus Diet Disease Drops Environment Epidemic Event Excretory function Exposure to Fatty acid glycerol esters Filtration Functional disorder Ganglia Glomerular Filtration Rate Health Care Costs Human Hypertension Infusion procedures Investigation Kidney Kidney Diseases Leptin Life Life Stress Life Style Maintenance Mediating Mentors Minor Modeling Molecular Mothers Nerve Obesity Organ Outcome Pathway interactions Pediatrics Perinatal Phase Phenylephrine Physiological Plasma Predisposition Proteins Public Health Rattus Receptor Activation Receptor, Angiotensin, Type 1 Renal Tissue Renal function Renin Renin-Angiotensin-Aldosterone System Reporting Research Risk Factors Rodent Secondary to Stress System Techniques Testing Therapeutic Variant adrenergic blood pressure regulation desensitization in vivo maternal separation novel premature pressure programs pup receptor expression response stressor vasoconstriction

项目摘要

PROJECT SUMMARY Chronic adult diseases, such as hypertension, diabetes or obesity, may develop as a consequence of early life stress (ELS). Adverse childhood events are highly correlated with enhanced cardiovascular response to a secondary stressor, a "second hit". Maternal separation is an established model of chronic behavioral stress in rodents that involves separating pups from their mothers 3 hr/day from days 2-14 of life. Adult maternally separated (MS) rats show lower glomerular filtration rate under baseline conditions compared to control, un-separated littermates, with no difference in blood pressure. Interestingly, the phenylephrine-induced vasoconstriction in the kidney is attenuated but the drop in blood pressure elicited by ganglion blockade is greater in MS rats. These data suggest increased sympathetic activation in MS rats. In contrast, the acute pressor response to angiotensin II (AngII) is comparable between MS and control rats whereas MS rats show exaggerated chronic AngII-induced hypertension. Thus, our data suggest that ELS impairs the ability of the kidney to control blood pressure following a "second hit". Taken together, we hypothesize that rats exposed to MS display increased renal sympathetic nerve activity (RSNA), which enhances vascular tone in the kidneys and impairs the physiological regulation of blood pressure. Given the fact that RSNA can increase AngII type 1 (AT1) receptor expression, we speculate that increased baseline RSNA in MS rats results in increased renal AngII system components, predisposing these rats to cardiovascular disease. In an original approach to model the growing epidemic of children with extremely poor dietary lifestyles, we exposed the rats to a high fat diet (HFD) as a secondary stressor. Our data show a fat-induced increase in blood pressure develops in rats exposed to ELS compared to control rats. Furthermore, we observed increased plasma leptin, corticosterone, aldosterone and renin activity in MS rats. These compelling data support the hypothesis that ELS impairs maintenance of blood pressure homeostasis in response to "second hits" in adult life. The mentored phase will focus on the investigation of the RSNA and AT1-dependent mechanisms by which ELS exacerbates AngII-induced hypertension in adult rats, followed by the independent phase focused on the study of mechanisms by which ELS exacerbates blood pressure sensitivity to a HFD in adult rats. This novel proposal will investigate the following four aims: (1) to test the hypothesis that increased RSNA impairs renal capacity to control blood pressure in response to chronic AngII infusion in adult MS rats; (2) to test the hypothesis that exaggerated AT1 receptor activation increases renal vasoconstriction and reduces basal renal filtration capacity, enhancing AngII-induced hypertension in adult MS rats; (3) To test the hypothesis that MS increases sensitivity of blood pressure in response to a HFD through a renal mechanism; and (4) To test the hypothesis that HFD increases AngII in adipose tissue and induces AT1 dependent increase in blood pressure in MS rats.

项目摘要慢性成人疾病，如高血压，糖尿病或肥胖症，可能会发展为早期的后果，生活压力（ELS）儿童期不良事件与增强的心血管反应高度相关，第二次压力源，“第二次打击”。母亲分离是一个建立的慢性行为应激模型，啮齿类动物，包括从生命的第2-14天起每天3小时将幼崽与其母亲分开。在基线条件下，成年母体分离（MS）大鼠显示较低的肾小球滤过率与对照、未分离的同窝仔相比，血压没有差异。有趣的是苯肾上腺素引起的肾血管收缩减弱，但苯肾上腺素引起的血压下降 MS大鼠的神经节阻滞更强。这些数据表明MS大鼠的交感神经激活增加。在相反，MS和对照大鼠对血管紧张素II（AngII）的急性升压反应相当而MS大鼠表现出过度的慢性AngII诱导的高血压。因此，我们的数据表明，ELS 损害肾脏在“二次打击”后控制血压的能力。总之，我们假设暴露于MS大鼠显示增加的肾交感神经活动（RSNA），增强肾脏中的血管张力并损害血压的生理调节。鉴于 RSNA可以增加血管紧张素Ⅱ 1型（AT 1）受体表达，我们推测，增加基线水平 MS大鼠中的RSNA导致肾AngII系统成分增加，使这些大鼠易于发生心血管疾病在一个原创的方法来模拟日益流行的儿童与极端贫困的饮食生活方式，我们将大鼠暴露于高脂肪饮食（HFD）作为次级应激源。我们的数据显示，与对照大鼠相比，暴露于ELS的大鼠血压升高。此外，我们还观察到，血浆瘦素、皮质酮、醛固酮和肾素活性。这些令人信服的数据支持 ELS损害成人血压稳态维持以响应“二次打击”假说生活指导阶段将侧重于研究RSNA和AT 1依赖性机制， ELS加重成年大鼠AngII诱导的高血压，随后是独立期， ELS加重成年大鼠血压对HFD敏感性的机制研究。这本小说该提案将研究以下四个目标：（1）测试RSNA增加损害肾功能的假设，在成年MS大鼠中响应于慢性AngII输注控制血压的能力;（2）测试过度的AT 1受体激活增加肾血管收缩并降低基础肾功能的假说过滤能力，增强AngII诱导的成年MS大鼠的高血压;（3）验证MS 通过肾脏机制增加血压对HFD的敏感性;以及（4）为了测试假设HFD增加脂肪组织中的AngII并诱导AT 1依赖性血压升高在MS大鼠。