Effect of Prenatal Programming on Renal Tubular Transport

产前规划对肾小管运输的影响

• 批准号: 7707197
• 负责人: MICHEL GERARD BAUM
• 金额: $ 33.91万
• 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 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7707197
• 关键词: 11-beta-Hydroxysteroid Dehydrogenases; 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; 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; deprivation; in vivo; lung maturation; pregnant; prenatal; prenatal exposure; programs; public health relevance; renal tubular transport; 11-beta-Hydroxysteroid Dehydrogenases; 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; 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; deprivation; in vivo; lung maturation; pregnant; prenatal; prenatal exposure; programs; public health relevance; 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侮辱。经常向孕妇施用产前糖皮质激素，以加速肺部肺部成熟。在初步数据中，我们发现，在胎儿发育过程中，在特定时间内将地塞米松给予孕妇的大鼠，导致当动物作为成年人研究时会导致高血压。虽然先前的研究假设并提供了间接证据，表明钠运输发生了变化，但尚未进行严格检查或直接检查。该提案的总体目标是确定产前侮辱计划如何在以后的生活中。我们旨在确定产前编程改变钠转运的机制。在初步数据中，我们表明，对孕妇大鼠的地塞米松给药会导致近端小管钠转运的增加。我们计划检查所涉及的肾单位段以及使用体外微灌注和体内微插入小管转运的机制。我们旨在确定产前地塞米松近端小管钠的近端钠转运是否通过近端小管肾上腺素 - 血管紧张素系统的失调。我们介绍了初步数据，表明产前编程会发生变化，并将直接检查内源性近端小管肾素 - 血管紧张素系统是否会介导大鼠产前编程改变的钠转运。在初步数据中，我们表明肾脏去神经导致暴露于点地塞米松的大鼠血压的归一化，而去神经并不影响对照动物的血压。我们的目的是检查通过肾脏神经支配改善血压的机制，如果这与肾内肾素 - 血管紧张素系统有关。最后，有两个广泛研究的高血压产前编程的模型。饮食蛋白剥夺和母体糖皮质激素暴露。这两个模型可能是由于孕妇大鼠的孕产妇饮食蛋白剥夺而导致胎盘较低的11？ - 羟基类固醇脱氢酶活性，并可能更大的胎儿暴露于母体糖皮质激素。我们将使孕产妇饮食蛋白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导致高血压的原因，肾单位数量的减少和因母体饮食蛋白的剥夺而改变了管状转运。公共卫生相关性：现在有实质性证据表明，高血压和心血管疾病可能是由于对发育中的胎儿造成的侮辱。经常向孕妇施用产前糖皮质激素，以加速肺部肺部成熟。我们表明，在胎儿发育期间在特定时期内给药时，产前地塞米松可能会导致高血压发育。该提案旨在确定产前地塞米松如何引起高血压。