ANTENATAL STEROID EXPOSURE AND RENAL SODIUM HANDLING

产前类固醇暴露和肾脏钠处理

• 批准号: 7904042
• 负责人: JORGE P FIGUEROA
• 金额: $ 25.39万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7904042
• 关键词: 14 year old; Accounting; Adrenal Cortex Hormones; Adult; Adverse effects; Age-Months; Animals; Betamethasone; Blood Pressure; Bumetanide; Cardiovascular Diseases; Consensus; Coronary heart disease; Coupling; Data; Defect; Development; Diastolic blood pressure; Disease; Dopamine; Dose; 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; Organ; Outcome Study; Pathway interactions; Perinatal; Perinatal Exposure; Physiological; Physiology; Play; Pregnancy; Premature Birth; Premature Labor; Process; Pump; Receptor Signaling; Recommendation; Regulation; Relative (related person); Role; SLC12A3 gene; Sheep; Sodium; Steroids; Stimulus; Structure; Testing; Tubular formation; United States National Institutes of Health; Woman; apical membrane; base; clinically relevant; cohort; critical period; dopamine system; epithelial Na+ channel; fetal; fetal programming; hypertensive heart disease; in utero; lung maturation; postnatal; pregnant; 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.

在妊娠晚期，糖皮质激素在器官成熟中起着重要作用，尤其是肺。因此，在NIH之后