Prenatal and Perinatal Programming of Adult Hypertension

描述（由申请人提供）：低出生体重是一个风险因素， 人类原发性高血压的发展。该项目的目标是 定义产前和围产期因素的机制， 高血压实验性成年高血压大鼠模型的建立 低出生体重已通过初步实验验证并将使用 对于所有研究。假设产前和围产期的激素印记 不可逆地改变了成熟肾脏的钠处理特性， 导致钠潴留、细胞外容积（ECV）扩张，以及 高血压这些研究将集中在肾脏的肾素-血管紧张素系统 (RAS)和皮质集合管（CCD），它们是 钠平衡将研究以下潜在机制： 将测量ECV以检验其在治疗期间扩张的假设。 高血压的发展。 肾内RAS持续上调， 出生会导致钠潴留这将通过确定 肾内RAS组分的表达在不同的时间点之前， 通过分子生物学方法， 还将测量全身血管紧张素I和血管紧张素II含量。 假设CCD钠转运是由于产前 血管紧张素II 1型受体，11-β-羟基类固醇 脱氢酶和/或盐皮质激素受体 片段分离的CCD将用于研究钠转运速率和 参与钠转运的特定基因和蛋白的表达 通路 为了评估减少钠过滤对发展的贡献， 高血压、总肾单位数、全肾和单个肾单位 将测量滤过率;此外，将测量总肾单位数。 使用产前维甲酸治疗。 根据初步实验，假设的发展， 产前程序性高血压可以在妊娠期间得到改善或预防。 将测试产后窗口。短期产后饮食和 对长期血压曲线的药理学操作将是 研究了

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.