Effect of Prenatal Programming on Renal Tubular Transport

描述（由申请人提供）：现在有实质性证据表明，高血压和心血管疾病可能是由于对发育中的胎儿造成的伤害。产前糖皮质激素常用于孕妇，以加速肺成熟。在初步数据中，我们发现，当动物作为成年动物进行研究时，在胎儿发育期间的特定时间对妊娠大鼠给予地塞米松会导致高血压。虽然以前的研究已经假设并提供了间接证据，表明钠转运发生了改变，但尚未进行严格或直接的检查。这项建议的总体目标是确定产前侮辱如何在以后的生活中编程高血压。我们的目的是通过产前程序来确定钠转运改变的机制。在初步的数据中，我们表明，产前给药地塞米松孕大鼠的结果在近端小管钠转运增加。我们计划通过体外微灌注和体内微穿刺来研究参与的肾单位片段和这种肾小管转运增加的机制。我们的目的是确定产前地塞米松增加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。我们目前的初步数据显示，有一个改变，在肾内的肾素-血管紧张素系统的产前编程，并将直接检查，如果内源性近端小管肾素-血管紧张素系统介导的改变钠转运的产前编程大鼠。在初步数据中，我们表明，肾脏去神经导致暴露于产前地塞米松的大鼠血压正常化，而去神经不影响对照动物的血压。我们的目的是研究肾脏去神经支配改善血压的机制，以及这是否与肾内肾素-血管紧张素系统有关。最后，有两个广泛研究的模式，产前规划的高血压，饮食蛋白质剥夺和母亲的糖皮质激素暴露。这两种模型可能是相关的，因为孕鼠母体膳食蛋白质缺乏导致胎盘11？羟基类固醇脱氢酶活性和潜在的更大的胎儿暴露于母体糖皮质激素。我们将分离母体膳食蛋白质剥夺与胎儿暴露于母体糖皮质激素，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转运改变与母体膳食蛋白质剥夺的原因。公共卫生相关性：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造成的伤害。产前糖皮质激素常用于孕妇，以加速肺成熟。我们表明，产前地塞米松可以导致高血压的发展时，在胎儿发育的特定时间管理。本提案旨在确定产前地塞米松如何引起高血压。

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.