Low Birth Weight, Blood Pressure, and Kidney Disease

项目摘要 低出生体重是高血压、心血管疾病和肾脏疾病的重要危险因素； 然而，不利的胎儿环境导致成人疾病风险的机制是 人们对此知之甚少。因为这个风险因素是在一个人的寿命开始时决定的，所以 更好地理解发育规划可以提供改善早期疾病的洞察力 预防和干预，以大大减轻成年后的疾病负担。小说 这一领域的发现也有很大的潜力来缩小健康差距，就像非裔美国人一样 不成比例地受到LBW和其他与此风险因素有关的疾病的影响，包括高血压 和慢性肾脏疾病。胎盘功能不全是西方LBW最常见的原因 先兆子痫的降低子宫灌流压(RUPP)动物模型模拟 在人类后代中看到的同样的健康影响，包括编程方式上的性别差异 影响心脏和肾脏疾病。有证据表明，肾脏炎症在糖尿病的发病中起着中介作用 高血压和肾脏损害之间的联系。这个项目的目标是研究这些影响 胎儿宫内发育受限(IUGR)子代慢性血压升高对肾脏健康的影响 并阐明发育过程中的变化导致儿童肾脏风险增加的机制。 在以后的生活中，以特定于性别的方式。这将通过诱导肾脏减少的二次损害来实现。 18月龄IUGR子代单肾切除后体重变化及生理指标的比较 对照组和IUGR患者肾功能及组织损伤的分子和组织学标志物 雄性和雌性。降压药和消炎药也将用于 确定早期干预是否可以防止这种对侮辱的肾脏损伤。目标1将 检验胎儿宫内生长受限会导致血压长期升高的假设 在男性中，随着年龄的增长，肾功能进行性加速下降，导致 增加生长受限大鼠对肾脏损伤的易感性。目标2将检验这一假设 宫内生长受限计划促进肾组织肿瘤坏死因子-α和转化生长因子-β1的上调 对继发性肾损害的反应有助于增加对肾损伤的易感性 生长受限的大鼠。

Project Summary Low birth weight (LBW) is an important risk factor for hypertension, cardiovascular and kidney disease; however, the mechanisms by which an adverse fetal environment programs risk for adult disease are poorly understood. Because this risk factor is determined at the beginning of a person’s lifespan, a better understanding of developmental programming can provide insight that improves early disease prevention and intervention to drastically reduce the burden of disease in later adulthood. Novel findings in this area also have great potential to reduce health disparities, as African-Americans are disproportionately affected by LBW and other conditions linked to this risk factor including hypertension and chronic kidney disease. Placental insufficiency is the most common cause of LBW in the Western world, and the reduced uterine perfusion pressure (RUPP) animal model of preeclampsia mimics the same health effects seen in human offspring, including the sex differences in how programming influences cardio-renal disease. Evidence suggests that renal inflammation plays a mediatorial role in the link between hypertension and kidney damage. The objective of this project is to study the effects of chronic elevations in blood pressure on renal health in intrauterine growth restricted (IUGR) offspring, and to elucidate the mechanisms by which changes during development lead to increased renal risk in later life in a sex-specific manner. This will be done by inducing a secondary insult of reduced renal mass by uni-nephrectomy in 18 month old IUGR offspring, and comparing physiological indicators of renal function as well as molecular and histological markers of tissue injury between control and IUGR males and females. Blood pressure-lowering and anti-inflammatory medications will also be used to determine whether early intervention can prevent this renal damage in response to an insult. Aim 1 will test the hypothesis that intrauterine growth restriction programs a long-term increase in blood pressure in males that initiates a progressive accelerated age-related decline in renal function leading to an enhanced susceptibility to renal injury in growth-restricted rats. Aim 2 will test the hypothesis that intrauterine growth restriction programs enhanced up-regulation of renal TNF-α and TGF-β1 in response to a secondary renal insult that contributes to enhanced susceptibility to renal injury in growth-restricted rats.