Prenatal and Perinatal Programming of Adult Hypertension

描述(由申请者提供)：低出生体重是导致 人类高血压病的发展。该项目的目标是 定义产前和围产期因素稍后进行编程的机制 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，并将用于 用于所有研究。假设是产前和围产期的荷尔蒙印记 不可逆转地改变了成熟肾脏的钠处理特性， 导致钠滞留，细胞外体积(ECV)膨胀，以及 高血压。这些研究将集中在肾脏肾素-血管紧张素系统上。 (RAS)和皮质集合管(CCD)，这是关键的调节 钠平衡。将调查以下可能的机制： 将测量ECV以检验其在 高血压的发展。 肾内RAS持续上调，术后未能正常消退 分娩会导致钠离子滞留。这将通过确定 肾内RAS组分在治疗前后不同时间点的表达 通过分子生物学方法发展为高血压后，肾脏和 还将测量全身血管紧张素I和血管紧张素II的含量。 推测胎儿期CCD钠转运上调 血管紧张素II 1型受体11-β-羟基类固醇的印迹 肾单位中的脱氢酶和/或盐皮质激素受体 细分市场。分离的CCDs将被用来研究钠的传输速率和 钠转运相关基因和蛋白的表达 路径。 评估低钠滤过对糖尿病发展的贡献 高血压、总肾单位数及全肾和单肾单位 将测量滤过率；同时，肾单位总数将为 胎儿期使用维甲酸治疗。 在初步实验的基础上，假设 产前程序性高血压可以在治疗期间改变或预防 将对产后窗口进行测试。产后短期饮食对母婴的影响 对长期血压曲线的药理学操作将是 调查过了。

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.