Prenatal and Perinatal Programming of Adult Hypertension

成人高血压的产前和围产期规划

• 批准号: 6750112
• 负责人: VESA MATTI VEHASKARI
• 金额: $ 11.89万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2004-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6750112
• 关键词: angiotensin receptor; animal birth weight; corticosteroid receptors; disease /disorder etiology; disease /disorder model; disease /disorder proneness /risk; early experience; hormone regulation /control mechanism; hypertension; laboratory rat; perinatal; renal tubular transport; renin angiotensin system; saluresis

DESCRIPTION (provided by applicant): Low birth weight is a risk factor for the development of human essential hypertension. The goal of the project is to define the mechanisms by which prenatal and perinatal factors program later hypertension. An experimental rat model of adult hypertension associated with low birth weight has been validated by preliminary experiments and will be used for all studies. The hypothesis is that pre- and perinatal hormonal imprinting irreversibly alters the sodium handling characteristic of the maturing kidney, resulting in sodium retention, expansion of extracellular volume (ECV), and hypertension. The studies will focus on the renal renin-angiotensin system (RAS) and the cortical collecting duct (CCD) which are critical regulators of sodium balance. The following potential mechanisms will be investigated: ECV will be measured to test the hypothesis that it is expanded during the development of hypertension. Persisting upregulation of intrarenal RAS and failure to regress normally after birth would lead to sodium retention. This will be examined by determining the intrarenal expression of the RAS components at different time points before and after the development of hypertension by molecular biology methods; renal and systemic angiotensin I and angiotensin II contents will also be measured. CCD sodium transport is hypothesized to be upregulated due to prenatal imprinting of the angiotensin II type 1 receptor, the 11-beta-hydroxysteroid dehydrogenase enzyme, and/or the mineralocorticoid receptor in this nephron segment. Isolated CCDs will be used to study the sodium transport rate and the expression of the specific genes and proteins involved in the Na transport pathway. To assess the contribution of reduced Na filtration to the development of hypertension, total nephron number as well as whole kidney and single nephron filtration rate will be measured; also, the total nephron number will be manipulated using prenatal retinoic acid treatment. Based on preliminary experiments, the hypothesis that the development of prenatally programmed hypertension can be modified or prevented during a postnatal window will be tested. The effect of short-term postnatal dietary and phamacological manipulations on the long-term blood pressure profile will be investigated.

描述（申请人提供）：低出生体重是 人类基本高血压的发展。该项目的目的是 定义产前和围产期因素以后计划的机制 高血压。与成人高血压的实验大鼠模型 低出生体重已通过初步实验验证，将被使用 所有研究。假设是前和围产期荷尔蒙印记 不可逆转地改变成熟肾脏的钠处理特征， 导致钠保留率，细胞外体积（ECV）的膨胀和 高血压。这些研究将重点放在肾素肾素 - 血管紧张素系统上 （RAS）和皮质收集管（CCD），它们是关键的调节剂 钠平衡。将研究以下潜在机制： 将测量ECV以检验以下假设。 高血压的发展。 持续上调肾内RA和未能正常退回 出生将导致钠保留。这将通过确定 RAS成分在不同时间点的肾内表达和 通过分子生物学方法发展高血压后；肾脏和 还将测量全身性血管紧张素I和血管紧张素II含量。 CCD钠转运被认为由于产前而被上调 血管紧张素II 1型受体的印迹，11β-羟基固醇 该肾单位中的脱氢酶酶和/或矿物皮质激素受体 部分。孤立的CCD将用于研究钠运输速率和 参与Na转运的特定基因和蛋白质的表达 路径。 评估降低NA过滤对开发的贡献 高血压，肾单位总数以及整个肾脏和单个肾单位 过滤率将测量；另外，总的肾单位数将是 使用产前视黄酸治疗进行操作。 基于初步实验，假设的发展 可以在产前编程的高血压进行修改或预防 产后窗口将进行测试。短期产后饮食和 长期血压轮廓上的流态性操纵将是 调查。