Low birth weight, the kidney, and hypertension

描述（由申请人提供）：大量流行病学研究报告低出生体重（LBW）与高血压风险呈负相关；然而，低体重与高血压之间的联系机制尚不清楚。众所周知，肾脏在动脉压的长期调节中起着重要作用。肾脏在高血压的形成过程中扮演着重要的角色，在大鼠肾形成或妊娠的最后三分之一给予母体蛋白限制，导致高血压LBW后代，这与肾素血管紧张素系统（RAS）和交感神经系统（SNS）的改变有关。因此，由妊娠期母体蛋白限制引起的胎儿营养不良的动物模型支持由于不利的胎儿环境而导致的高血压编程的作用。在人类中，由于子宫胎盘灌注减少或母体营养不良导致的营养输送不足，胎儿营养不良会限制胎儿生长并导致小胎龄新生儿。由于西方世界的LBW更可能是子宫胎盘灌注受损而不是母体营养不良的结果，我们开发了一种独特的体内胎盘功能不全模型来研究LBW与高血压之间的关系。具体来说，妊娠后期引起的子宫灌注减少导致足月出生的LBW后代出现高血压，并且根据初步数据，RAS和SNS均出现改变。因此，在胎儿发育的关键时期，对氧气和营养限制的适应可能导致编程，从而激活RAS和SNS，从而导致高血压的发生。因此，我们将利用我们的新动物模型来验证中心假设，即LBW后代的高血压是由RAS和SNS的异常引发和维持的。为了验证这一假设，我们计划表征RAS和SNS的时间变化，并利用分子和生理学方法直接评估这些系统在高血压发病机制中的作用。需要解决的具体目标是：1。验证RAS异常介导LBW子代高血压的假说。2. 验证SNS异常介导LBW子代高血压的假说。3. 确定SNS和RAS在LBW后代高血压介导中的时间相互作用。

DESCRIPTION (provided by applicant): Numerous epidemiological studies report an inverse relationship between low birth weight (LBW) and the risk of hypertension; however, the mechanisms linking LBW and hypertension remain unclear. The kidneys are known to play an important role in the long-term regulation of arterial pressure. An important role for the kidneys in the programming of hypertension is suggested as maternal protein restriction administered during nephrogenesis or the last third of gestation in the rat, results in hypertensive LBW offspring that are associated with alterations in the renin angiotensin system (RAS) and the sympathetic nervous system (SNS). Thus, animal models of fetal malnutrition induced by maternal protein restriction during gestation support a role for programming of hypertension due to an adverse fetal environment. In humans, fetal malnutrition, due to either an insufficient nutrient delivery via reduced uteroplacental perfusion or maternal undernutrition, limits fetal growth and results in small-for-gestational-age newborn. As LBW within the Western world is more likely the result of impaired uteroplacental perfusion rather than maternal malnutrition, we have developed a unique model of in vivo placental insufficiency to examine the association between LBW and hypertension. Specifically, reduced uterine perfusion induced during late gestation in the rat results in LBW offspring born at term that develop hypertension, and based on preliminary data, exhibit alterations in both the RAS and SNS. Thus, adaptations to oxygen and nutrient restriction during a critical period of fetal development may lead to programming with resulting activation of the RAS and SNS leading to the development of hypertension. Thus, we will utilize our novel animal model to test the central hypothesis that hypertension in LBW offspring is initiated and sustained by abnormalities in the RAS and the SNS. To test this hypothesis, we plan to characterize temporal changes in the RAS and SNS, and directly assess the role of these systems in the pathogenesis of the hypertension utilizing molecular and physiological methods. Specific aims to be addressed are: 1. To test the hypothesis that abnormalities in the RAS mediate the hypertension in LBW offspring. 2. To test the hypothesis that abnormalities in the SNS mediate the hypertension in LBW offspring. 3. To determine the temporal interactions between the SNS and the RAS in mediating hypertension in LBW offspring.