ANTENATAL STEROID EXPOSURE AND RENAL SODIUM HANDLING

在妊娠后期，糖皮质激素在器官成熟，尤其是肺的成熟中起着至关重要的作用。因此，在NIH之后 指南建议，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，有几条证据表明，产前类固醇在晚年可能会产生不良影响。 我们假设母体给予合成糖皮质激素以促进胎儿肺成熟有一个胎儿 程序化对肾脏钠处理的影响，导致成人生活中高血压的发展。 具体地说，我们关于高血压发病机制的假设是：1)暴露于 糖皮质激素在胎儿生命的关键时期改变肾脏成熟过程，导致肾脏功能增强。 部分钠重吸收；2)肾内多巴胺系统的调节失调是导致 与产前激素暴露相关的钠重吸收增加；以及3)糖皮质激素的应用 通过改变一种或多种基因的表达和/或调节来干扰肾脏成熟和随后的钠排泄 更多的钠离子转运体。具体地说，Na，K-ATPase泵，Na/H交换器(NHE-3)，布美他尼敏性 钠-钾-二氯共转运体(BSC1)、硫化物敏感的钠-氯共转运体(TSC)与盐皮质激素 敏感上皮钠通道(ENAC)。我们将通过给予临床相关剂量的 与临床使用的胎龄相同的怀孕绵羊的倍他米松。专门测试 这些假设，在SA 1中，我们将确定胎儿暴露于倍他米松是否会导致盐敏症的发生 成年后的高血压；在SA 2中，我们将确定产前类固醇是否会降低利钠效果 以及缺陷是否存在于受体信号和/或偶联的水平；在SA 3中，我们将 确定钠排泄减少和后续发展的具体途径(S) 盐敏感型高血压。这些数据将提供有关以下潜在不利影响的重要信息 产前激素暴露对肾脏钠处理机制的影响，并将开始阐明 糖皮质激素发挥了这种作用。

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.