ANTENATAL STEROID EXPOSURE AND RENAL SODIUM HANDLING

产前类固醇暴露和肾脏钠处理

• 批准号: 7714592
• 负责人: JORGE P FIGUEROA
• 金额: $ 14.57万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7714592
• 关键词: Accounting; Adrenal Cortex Hormones; Adult; Adverse effects; Age-Months; Age-Years; Animals; Betamethasone; Blood Pressure; Bumetanide; Cardiovascular Diseases; Consensus; Coronary heart disease; Coupling; Data; Defect; Development; Diastolic blood pressure; Disease; Dopamine; Dose; Elevation; Epidemiologic Studies; Event; Excretory function; Exposure to; Fetal Growth; Fetal Lung; Fetus; Fibrinogen; Gestational Age; Glucocorticoids; Guidelines; Hypertension; Individual; Kidney; Life; Lung; Malnutrition; Membrane Transport Proteins; Metabolism; Mineralocorticoids; Na(+)-K(+)-Exchanging ATPase; Numbers; Organ; Outcome Study; Pathway interactions; Patient currently pregnant; Perinatal; Perinatal Exposure; Physiological; Physiology; Play; Pregnancy; Premature Birth; Premature Labor; Process; Pump; Rate; Receptor Signaling; Recommendation; Regulation; Relative (related person); Role; SLC12A3 gene; Sheep; Sodium; Steroids; Stimulus; Structure; Testing; Tubular formation; United States National Institutes of Health; Week; Woman; apical membrane; base; clinically relevant; cohort; critical developmental period; dopamine system; epithelial Na+ channel; fetal; fetal programming; hypertensive heart disease; in utero; lung maturation; prenatal; programs; response; salt sensitive; saluretic; young adult

Late in gestation glucocorticoids play an essential role in organ maturation, particularly the lung. Thus, following NIH guidelines recommendations, a large number of women threatened with premature delivery are treated with synthetic glucocorticoids. However, several lines of evidence suggest possible adverse effects of antenatal steroids later in life. We hypothesize that maternal administration of synthetic glucocorticoids to promote fetal lung maturation has a fetal programming effect on renal sodium handling that results in the development of hypertension in adult life. Specifically, our hypotheses regarding putative mechanisms for the development of hypertension are: 1) Exposure to glucocorticoids, at critical periods during fetal life, alters renal maturation processes resulting in kidneys with enhanced fractional sodium reabsorption; 2) Dysregulation of the intrarenal dopamine system is a major contributor for the enhanced sodium reabsorption associated with antenatal steroid exposure; and 3) Glucocorticoid administration disrupts renal maturation and subsequently sodium excretion by altering the expression and/or regulation of one or more of the sodium transporters. Specifically, the Na,K-ATPase pump,the Na/H exchanger (NHE-3), the bumetanidesensitive Na-K-2Cl cotransporter (BSC1), the thiazide-sensitive Na-Cl cotransporter (TSC) and the mineralocorticoid sensitive Epithelial Na Channel (EnaC). We will test these hypotheses by administering clinically relevant doses of betamethasone to pregnant sheep at a gestational age equivalent to that when is used clinically. To specifically test these hypotheses, in SA 1 we will determine if fetal exposure to betamethasone results in the development of saltsensitive hypertension during adult life; In SA 2 we will determine if antenatal steroids decrease the natriuretic effect of dopamine and whether the defect lies at the level of receptor signaling and/or coupling; and in SA 3 we will determine the specific pathway(s) that can account for a decrease in sodium excretion and the subsequent development of salt-sensitive hypertension. These data will provide important information regarding the potential adverse effects of antenatal steroid exposure on renal sodium handling mechanisms and will begin to elucidate the mechanisms by which glucocorticoids exerts this effect.

妊娠晚期糖皮质激素在器官成熟中起重要作用，特别是肺。因此，在NIH 根据指南的建议，大量面临早产威胁的妇女接受合成药物治疗， 糖皮质激素然而，一些证据表明，产前类固醇可能对以后的生活产生不利影响。 我们假设母体给予合成糖皮质激素以促进胎肺成熟， 对肾钠处理的编程效应，导致成年后高血压的发展。 具体而言，我们关于高血压发展的假定机制的假设是：1）暴露于 糖皮质激素，在胎儿生命的关键时期，改变肾成熟过程，导致肾脏增强 钠重吸收分数; 2）肾内多巴胺系统的失调是导致肾内多巴胺水平升高的主要原因。 与产前类固醇暴露相关的钠重吸收增强;和3）糖皮质激素给药 通过改变一种或多种蛋白的表达和/或调节， 更多的钠转运蛋白。具体而言，Na，K-ATP酶泵，Na/H交换器（NHE-3），布美他尼敏感的 Na-K-2Cl协同转运蛋白（BSC 1）、噻嗪敏感性Na-Cl协同转运蛋白（TSC）和盐皮质激素 敏感性上皮Na通道（EnaC）。我们将通过给予临床相关剂量的 更好地应用于妊娠期与临床使用时相当的妊娠绵羊。专门测试 这些假设，在SA 1中，我们将确定胎儿暴露于beta2是否会导致盐敏感性的发展， 成年期高血压;在SA 2中，我们将确定产前类固醇是否会降低利钠利尿作用 多巴胺和缺陷是否位于受体信号传导和/或耦合的水平;在SA 3中，我们将 确定可解释钠排泄减少和后续发展的特定途径 盐敏感性高血压这些数据将提供有关潜在不利影响的重要信息， 产前类固醇暴露对肾钠处理机制的影响，并将开始阐明 糖皮质激素发挥这种作用。