Effect of Prenatal Programming on Renal Tubular Transport

描述(申请人提供)：现在有实质性的证据表明，高血压和心血管疾病可能是由于对发育中的胎儿施加的侮辱造成的。孕妇经常在产前使用糖皮质激素，以促进肺成熟。在初步的数据中，我们发现在胚胎发育的特定时间给怀孕的大鼠服用地塞米松会导致高血压，当动物作为成年动物进行研究时。虽然以前的研究已经假设并提供了间接证据，表明钠转运发生了变化，但这一点并未得到批判性或直接的检验。这项提案的总体目标是确定产前侮辱计划高血压在以后的生活中是如何进行的。我们的目标是通过产前编程来确定钠转运改变的机制。在初步数据中，我们显示孕鼠产前服用地塞米松会导致近曲小管钠转运增加。我们计划使用体外微灌流和体内微穿刺法检查肾单位节段和肾小管转运增加的机制。我们的目标是确定产前地塞米松增加的近端小管钠转运是否是通过近端小管肾素-血管紧张素系统的失调。我们提供的初步数据表明，通过产前编程，大鼠肾内肾素-血管紧张素系统发生了变化，并将直接检查内源性近端小管肾素-血管紧张素系统是否通过产前编程介导了改变的钠转运。在初步数据中，我们显示，去肾神经导致出生前接触地塞米松的大鼠血压正常化，而去神经对对照组动物的血压没有影响。我们的目标是研究去肾神经对血压改善的机制，以及这是否与肾内肾素-血管紧张素系统有关。最后，有两个被广泛研究的高血压产前规划模型：饮食蛋白质剥夺和母体糖皮质激素暴露。这两种模型可能是相关的，因为妊娠大鼠缺乏母体蛋白质会导致胎盘11？羟基类固醇脱氢酶活性降低，并有可能增加胎儿对母体糖皮质激素的暴露。我们将把母体膳食蛋白质缺乏与胎儿接触母体糖皮质激素分离，以确定母体糖皮质激素暴露是否是高血压、肾单位数量减少和肾小管运输改变与母体膳食蛋白质缺乏的原因。与公共卫生相关：现在有大量证据表明，高血压和心血管疾病可能是对发育中的胎儿施加的侮辱造成的。孕妇经常在产前使用糖皮质激素，以促进肺成熟。我们发现，如果在胎儿发育的特定时间给予地塞米松，产前地塞米松会导致高血压的发生。该提案旨在确定产前地塞米松是如何导致高血压的。

DESCRIPTION (provided by applicant): There is now substantive evidence that hypertension and cardiovascular disease may result from insults that are inflicted on the developing fetus. Prenatal glucocorticoids are frequently administered to pregnant women to accelerate pulmonary lung maturation. In preliminary data we have found that administration of dexamethasone to pregnant rats at specific times during fetal development results in hypertension when the animals were studied as adults. While previous studies have hypothesized and provided indirect evidence that there is an alteration in sodium transport, this has not been critically or directly examined. The overall goal of this proposal is to determine how prenatal insults program hypertension in later life. We aim to determine the mechanism of the altered sodium transport by prenatal programming. In preliminary data we show that prenatal administration of dexamethasone to pregnant rats results in an increase in proximal tubule sodium transport. We plan to examine the nephron segments involved and the mechanism for this increase in tubule transport using in vitro microperfusion and in vivo micropuncture. We aim to determine if the increased proximal tubule sodium transport by prenatal dexamethasone is via dysregulation of the proximal tubule renin- angiotensin system. We present preliminary data showing that there is an alteration in the intrarenal renin-angiotensin system by prenatal programming and will examine directly if the endogenous proximal tubule renin-angiotensin system mediates the altered sodium transport by prenatal programming in rats. In preliminary data we show that renal denervation results in a normalization of the blood pressure in rats exposed to prenatal dexamethasone, while denervation did not affect the blood pressure in control animals. We aim to examine the mechanism for the amelioration in blood pressure by renal denervation and if this is linked to the intrarenal renin-angiotensin system. Finally, there are two widely studied models for prenatal programming of hypertension; dietary protein deprivation and maternal glucocorticoid exposure. These two models may be connected since maternal dietary protein deprivation in pregnant rats leads to lower placental 11 ?-hydroxysteroid dehydrogenase activity and potentially greater fetal exposure to maternal glucocorticoids. We will dissociate maternal dietary protein deprivation from fetal exposure to maternal glucocorticoids to determine if maternal glucocorticoid exposure is the cause for hypertension, a reduction in nephron number and altered tubular transport with maternal dietary protein deprivation. PUBLIC HEALTH RELEVANCE: There is now substantive evidence that hypertension and cardiovascular disease may result from insults that are inflicted on the developing fetus. Prenatal glucocorticoids are frequently administered to pregnant women to accelerate pulmonary lung maturation. We show that prenatal dexamethasone can result in the development of hypertension when administered during specific times during fetal development. This proposal aims to determine how prenatal dexamethasone causes hypertension.