Effect of Prenatal Programming on Renal Tubular Transport

产前规划对肾小管运输的影响

• 批准号: 8319557
• 负责人: MICHEL GERARD BAUM
• 金额: $ 30.12万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8319557
• 关键词: Address; Adult; Affect; Animals; Biological Assay; Blood Pressure; Cardiovascular Diseases; Control Animal; Coupled; Data; Denervation; Development; Dexamethasone; Dietary Proteins; Distal; Elderly; Exposure to; Fetal Development; Fetus; Glucocorticoids; Goals; Health; Hydroxysteroid Dehydrogenases; Hypertension; In Vitro; Kidney; Link; Lung; Maternal Deprivation; Mediating; Micropuncture; Modeling; Mothers; Nephrons; Nerve; Perinatal Exposure; Pregnant Women; Proteins; Rattus; Renin-Angiotensin System; Sodium; Steroids; Study models; Techniques; Time; Tubular formation; Up-Regulation; adverse outcome; deprivation; in vivo; lung maturation; pregnant; prenatal; prenatal exposure; programs; renal tubular transport

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.

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而引起的。孕妇经常服用产前糖皮质激素以加速肺成熟。在初步数据中，我们发现，当对成年大鼠进行研究时，在胎儿发育过程中的特定时间给怀孕大鼠施用地塞米松会导致高血压。虽然之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，但这还没有经过严格或直接的检验。该提案的总体目标是确定产前侮辱如何影响以后的高血压。我们的目标是通过产前编程确定钠转运改变的机制。在初步数据中，我们表明，对怀孕大鼠产前给予地塞米松会导致近端小管钠转运增加。我们计划使用体外微灌注和体内微穿刺​​来检查所涉及的肾单位段以及肾小管运输增加的机制。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-血管紧张素系统失调所致。我们提供的初步数据表明，产前编程导致肾内肾素-血管紧张素系统发生改变，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大鼠钠转运的改变。在初步数据中，我们表明去肾神经导致暴露于产前地塞米松的大鼠血压正常化，而去肾神经并不影响对照动物的血压。我们的目的是研究通过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，有两种广泛研究的高血压产前规划模型；膳食蛋白质缺乏和母亲糖皮质激素暴露。这两个模型可能是相关的，因为怀孕大鼠的母体膳食蛋白质剥夺会导致胎盘 11β-羟基类固醇脱氢酶活性降低，并且胎儿可能会更多地接触母体糖皮质激素。我们将母亲膳食蛋白质剥夺与胎儿接触母亲糖皮质激素分开，以确定母亲糖皮质激素暴露是否是高血压、肾单位数量减少以及母亲饮食蛋白质剥夺引起的肾小管运输改变的原因。公众健康相关性：现在有实质性证据表明，高血压和心血管疾病可能是由发育中的胎儿受到的伤害引起的。孕妇经常服用产前糖皮质激素以加速肺成熟。我们发现，在胎儿发育过程中的特定时间服用产前地塞米松可导致高血压的发生。该提案旨在确定产前地塞米松如何导致高血压。