Prenatal Glucocorticoid and Postnatal Blood Pressure

产前糖皮质激素和产后血压

• 批准号: 6690767
• 负责人: JORGE Pablo FIGUEROA
• 金额: $ 36万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-12-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6690767
• 关键词: cell growth regulation; chemical structure function; developmental genetics; disease /disorder prevention /control; disease /disorder proneness /risk; drug adverse effect; embryo /fetus; embryo /fetus drug adverse effect; embryo /fetus protein; embryo /fetus therapy; gene expression; glucocorticoids; histogenesis; hormone regulation /control mechanism; hormone therapy; hypertension; iatrogenic disease; kidney disorder; longitudinal animal study; lung disorder; nephrectomy; nonhuman therapy evaluation; renal tubule; renin angiotensin system; respiratory disease /disorder therapy; sheep

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.

描述（由申请人提供）：在开发过程中，糖皮质激素（GC） 对于器官成熟至关重要，尤其是胎儿肺。 1994 年 NIH 共识小组建议使用糖皮质激素增强胎儿肺功能 24 至 34 周之间受早产威胁的妊娠成熟 妊娠期。因此，使用单剂量或多剂量 GC 此类怀孕的比例已从 15% 增加到 50% 以上。这 GC可能产生不利影响的可能性引发了质疑 GC 在围产期的使用越来越多。我们的工作假设是 母体GC治疗促进胎儿肺成熟具有胎儿编程 对肾脏的影响将在以后的生活中表现为高血压。 具体来说，我们的假设是：1) 合成 GC 的产前给药 使个体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会破坏肾发生 导致肾脏肾单位数量减少； 3) 合成气相色谱 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影响的肾内机制 胎儿 RAS 包括对致密斑中 COX-2 和 I 型 NOS 的抑制， 肾组织中血管紧张素AT1和AT2受体的下调； 5） 胎儿期肾单位数量减少会导致胎儿期高血压 成年期。我们将通过管理单个或多个 妊娠羊在妊娠期倍他米松的临床相关剂量 年龄相当于临床实践中使用的年龄（妊娠的 0.6 岁）。到 特别测试是否在这个特定阶段减少肾单位质量 成人发育产生高血压，我们会进行胎儿单侧 妊娠 0.6 时进行肾切除术并监测血压和肾功能 出生后直至成年后按选定的时间间隔进行。此外，利用分子 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 系统以及胎儿发育过程中该系统的两个重要调节器， 即 I 型 NOS 和 PGHS-2。这些数据将提供重要信息 产前 GC 给药对成人血压的潜在影响 生命以及GC发挥这种作用的机制。