Prenatal Glucocorticoid and Postnatal Blood Pressure

性状（由申请方提供）：在开发期间，糖皮质激素（GC） 对器官的成熟至关重要，尤其是胎儿的肺。1994年， 共识小组建议使用糖皮质激素来增强胎儿肺 在24至34周之间受到早产威胁的妊娠中的成熟 妊娠期。因此，单次或多次给予GC 从15%上升到50%以上。的 GC可能产生不利影响的可能性促使人们质疑 围产期越来越多地使用GC。我们的假设是 母体GC治疗促进胎肺成熟具有胎儿程序性 对肾脏的影响，在以后的生活中会表现为高血压。 具体而言，我们的假设是：1）合成GC的宫内给药 使个体在成年后易患高血压; 2）暴露于 在胎儿生命的关键时期，合成GC会破坏肾发生 导致肾单位数量减少的肾脏; 3）合成GC 通过下调胎儿肾素血管紧张素系统破坏肾发生 (RAS)4）合成GC对大鼠肾脏的作用机制 胎儿RAS包括致密斑中考克斯-2和I型NOS的抑制， 肾组织中血管紧张素AT 1和AT 2受体的下调; 5） 胎儿期肾单位数量减少导致高血压 成年我们将通过单次或多次给药来验证这些假设。 妊娠期妊娠绵羊的临床相关剂量 与临床实践中使用的年龄相当（妊娠期0.6）。到 专门测试是否在这个特定阶段减少肾单位质量 发育产生高血压的成年人，我们将执行胎儿单侧 孕0.6时行肾切除术，并监测血压和肾功能 在出生后的特定时间间隔，直到成年。此外，使用分子 生物学工具，我们将研究潜在的机制，GC可能会改变胎儿 肾脏发育具体来说，我们将研究RAS的表达 在胎儿发育过程中， 也就是说，I型NOS和PGHS-2。这些数据将提供重要信息， 产前应用GC对成人血压潜在影响 生命和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.