Prenatal Glucocorticoid and Postnatal Blood Pressure

描述(申请人提供)：在发育过程中，糖皮质激素(GC) 对器官成熟是必不可少的，尤其是胎儿的肺。1994年，美国国立卫生研究院 专家小组一致建议使用糖皮质激素增强胎儿肺功能 24至34周早产孕妇的成熟度 怀孕的感觉。因此，GC的使用是单次或多次给药 在这类怀孕中从15%增加到50%以上。这个 GC可能会产生不良影响的可能性促使人们对 围产期糖皮质激素的使用日益增多。我们的工作假设是 孕妇GC疗法促进胎儿肺成熟有胎儿程序化 对肾脏的影响，在以后的生活中会出现高血压。 具体地说，我们的假设是：1)产前服用合成GC 使个人在成年后易患高血压；2)暴露于 合成GC在胎儿生命的关键时期扰乱肾脏发生 导致肾脏中肾单位数量减少；3)合成GC 通过下调胎儿肾素血管紧张素系统干扰肾脏发生 (RAS)；4)合成GC影响肾内的机制 胎儿RAS包括抑制致密斑内COX-2和I型一氧化氮合酶 肾组织血管紧张素AT1、AT2受体表达下调； 胎儿期肾单位数量减少会导致高血压 成人期。我们将通过单一或多个实施来检验这些假设 妊娠绵羊应用倍他米松的临床相关剂量 年龄相当于临床使用的年龄(妊娠期的0.6)。至 具体测试在这一特定阶段是否减少肾单位质量 发育导致成人高血压，我们将进行单侧胎儿手术 妊娠0.6天行肾切除术，监测血压和肾功能 在出生后选定的时间间隔，直到成年。此外，使用分子 生物学工具我们将研究GC可能改变胎儿的潜在机制 肾脏发育。具体来说，我们将研究RAS的表达 该系统以及该系统在胎儿发育过程中的两个重要调节器， 即I型一氧化氮合酶和PGHS-2。这些数据将提供有关 产前应用糖皮质激素对成人血压的潜在影响 寿命和GC发挥这种作用的机制。

DESCRIPTION (provided by applicant): During development, glucocorticoids (GC) are essential for organ maturation, particularly the fetal lung. In 1994 an NIH consensus panel recommended the use of glucocorticoids for enhancing fetal lung maturation in pregnancies threatened by premature labor between 24 and 34 weeks of gestation. As a consequence, the use of GC given as single or multiple doses has increased from 15 percent to more than 50 percent in such pregnancies. The possibility that GC may have adverse effects has prompted the questioning of the growing use of GC in the perinatal period. Our working hypothesis is that maternal GC therapy to promote fetal lung maturation has a fetal programming effect on the kidney that will appear as hypertension later in life. Specifically, our hypotheses are: 1) Antenatal administration of synthetic GC predisposes the individual to hypertension in adult life; 2) Exposure to synthetic GC, at critical periods during fetal life, disrupts nephrogenesis resulting in kidneys with a reduced number of nephrons; 3) Synthetic GC disrupts nephrogenesis by downregulating the fetal ReninAngiotensin-System (RAS); 4) The intrarenal mechanism involved in the effects of synthetic GC on the fetal RAS includes inhibition of COX-2 and Type I NOS in macula densa and the downregulation of angiotensin AT1 and AT2 receptors in renal tissue; 5) Reduction in nephron number during fetal life results in hypertension during adulthood. We will test these hypotheses by administering single or multiple clinically relevant doses of betamethasone to pregnant sheep at a gestational age equivalent to that used in clinical practice (0.6 of gestation). To specifically test whether reducing nephron mass at this specific stage of development produces hypertension in adults, we will perform fetal unilateral nephrectomy at 0.6 of gestation and monitor blood pressure and renal function at selected intervals after birth until adulthood. In addition, using molecular biology tools we will study potential mechanisms by which GC may alter fetal kidney development. Specifically, we will study the expression of the RAS system and of two important regulators of this system during fetal development, i.e., Type I NOS and PGHS-2. These data will provide important information on the potential impact of prenatal GC administration on blood pressure in adult life and the mechanism by which GC exerts this effect.