Low Birth Weight, Blood Pressure, and Kidney Disease

低出生体重、血压和肾脏疾病

• 批准号: 9378059
• 负责人: Ashley Denise Newsome
• 金额: $ 3.25万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-25 至 2019-09-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9378059
• 关键词: 1 year old; Address; Adult; Affect; African American; Age; Age-Months; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Area; Birth Weight; Blood Pressure; Cardiovascular Diseases; Chronic; Chronic Kidney Failure; Complement; Data; Development; Disease; Early Intervention; Elderly; Environment; Etiology; Exhibits; Experimental Models; Exposure to; Female; Fetal Growth; Fetal Growth Retardation; Glomerular Filtration Rate; Growth; Health; Histologic; Human; Hypertension; Inflammation; Inflammatory; Injury; Kidney; Kidney Diseases; Kidney Neoplasms; Laboratories; Lead; Life; Link; Longevity; Low Birth Weight Infant; Mediating; Mississippi; Modeling; Molecular; Morbidity - disease rate; Nephrectomy; Nephrons; Non-Insulin-Dependent Diabetes Mellitus; Perfusion; Persons; Pharmaceutical Preparations; Physiological; Placental Insufficiency; Play; Population; Pre-Eclampsia; Predisposition; Prevalence; Prevention strategy; Preventive Intervention; Process; Rattus; Renal Mass; Renal function; Reporting; Research; Risk; Risk Factors; Role; Sex Characteristics; TGFB1 gene; TNF gene; Techniques; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Up-Regulation; Weight Gain; Western World; age related; burden of illness; cytokine; disorder prevention; epidemiologic data; fetal; health disparity; improved; insight; mRNA Expression; male; modifiable risk; mortality; novel; offspring; pressure; prevent; programs; response; sex; young adult

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.

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， 不太了解。由于这种风险因素是在一个人的生命开始时确定的， 更好地理解发育程序可以提供改善早期疾病的见解 预防和干预，以大幅减少成年后期的疾病负担。小说 这一领域的研究结果也有很大的潜力，以减少健康差距，因为非洲裔美国人是 不成比例地受到LBW和与此风险因素相关的其他疾病（包括高血压）的影响 和慢性肾病。胎盘功能不全是西方国家LBW最常见的原因。 子宫灌注压降低（RUPP）先兆子痫动物模型模拟了 在人类后代中看到的相同的健康影响，包括编程方式的性别差异 影响心肾疾病。有证据表明，肾脏炎症在肾脏疾病中起着介导作用。 高血压和肾损伤之间的联系这个项目的目的是研究 慢性血压升高对宫内生长受限（IUGR）后代肾脏健康的影响， 并阐明发育过程中的变化导致肾脏风险增加的机制， 以一种特定的方式来表达。这将通过诱导减少肾功能的二次损伤来完成。 对18个月龄IUGR子代行单侧肾切除术， 肾功能以及组织损伤的分子和组织学标志物在对照和IUGR之间 雄性和雌性。降血压和抗炎药物也将用于 确定早期干预是否可以预防这种对损伤的反应。目标1将 检验子宫内生长受限导致血压长期升高的假设 在男性中，启动肾功能的进行性加速年龄相关性下降，导致 增加生长受限大鼠对肾损伤的易感性。目标2将检验以下假设： 宫内生长限制程序增强了肾肿瘤坏死因子-α和TGF-β1的上调， 对继发性肾损伤的反应，导致对肾损伤的易感性增加， 生长受限的老鼠