Fetal Origins of Adult Hypertension in Microswine

小型猪成年高血压的胎儿起源

• 批准号: 7007340
• 负责人: Susan P Bagby
• 金额: $ 27.56万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7007340
• 关键词: angiotensin /renin /aldosterone hypertension; angiotensin receptor; biological signal transduction; body composition; developmental genetics; developmental nutrition; dietary proteins; epidermal growth factor; glomerular filtration rate; growth factor receptors; hemodynamics; kidney function; miniature swine; nutrient intake activity; peptidyl dipeptidase A; protein deficiency; renal tubule; transcription factor

DESCRIPTION (provided by applicant): Human cardiovascular disease, including hypertension, has been linked by epidemiologic studies to low birth weight. Microswine offspring of 1% Maternal Protein Restriction (MPR), applied during last third of gestation plus first two wks of lactation (nephrogenic period), exhibit early asymmetric growth retardation, reduced nephron number, rapid catch-up growth, and adult hypertension (HTN); single-nephron hyperfiltration maintains normal total kidney function. Adult Low-Protein Offspring (LPO) show key Renin/AnglI (RAS) abnormalities vs Normal-Protein Offspring (NPO): 1) elevated intrarenal AnglI, suggesting increased AnglI generation; and 2) increased renal microvascular contractile reactivity to AnglI despite reduced AT1 receptor (AT1R) density, suggesting post-receptor enhancement of AT1R contractile signaling efficiency. Aim 1 will test the hypothesis that MPR leads to HTN via increased generation of intrarenal AnglI in adult LPO. SubAims will test whether: 1A) MPR-related HTN is associated with in vivo ECV excess; 1B) MPR leads to intrarenal AnglI excess or activates AnglI-generating elements: renin, angiotensinogen (Aogn), AnglI Converting Enzyme (ACE); and 1C) MPR induces increased renal vascular contractile reactivity to AnglI, either by reduced endothelial relaxation and/or by enhanced post-receptor signaling [via classic AT1R contractile pathways vs AT1R-dependent EGFR transactivating pathways]. In other states of non-inflammatory nephron deficit, compensatory single-nephron hyperfiltration - designed to maintain adequate protein/nitrogen excretion - requires intrarenal Renin/AnglI (RAS) activation. Thus, AIM 2 will test the hypothesis that Body-Size Excess relative to reduced nephron number - developing during rapid catch-up growth - induces the hemodynamic and RAS abnormalities in adult LPO. SubAims will test whether prevention of body size excess (by caloric restriction to maintain body wt percentile at the neonatal level) prevents: 2A. HTN/ECV excess/nephron hyperfiltration; 2B. intrarenal AnglI excess and/or activation of AnglI-generating elements; and 2C. increased renal vascular reactivity to AnglI. AIM 3 will test the hypothesis that effects of MPR and/or Body-Size Excess are mediated by the AT1 receptor. Subaims will test effects of in vivo AT1R blockade or placebo 3A. on hemodynamic and 3B. on AnglI contractile signaling via classic and EGFR-transactivation routes (using renal vascular reactivity and activated vs total signaling protein abundance in fresh vascular/cortical tissues). Studies address a worldwide health risk, test interventions (weight control/AT1R block) of potential clinical value, and impact the current pediatric practice of promoting catch-up growth in low-birth-wt infants.

描述（由申请人提供）：流行病学研究表明，人类心血管疾病（包括高血压）与低出生体重有关。在妊娠的最后三分之一加上哺乳期的前两周（肾源期）应用1%母体蛋白限制（MPR）的小型猪后代表现出早期不对称生长迟缓、肾单位数量减少、快速追赶生长和成年高血压（HTN）;单肾单位超滤维持正常的总肾功能。与正常蛋白后代（NPO）相比，成年低蛋白后代（LPO）显示关键的肾素/AnglI（RAS）异常：1）肾内AnglI升高，表明AnglI产生增加;和2）尽管AT 1受体（AT 1 R）密度降低，但肾微血管对AnglI的收缩反应性增加，表明AT 1 R收缩信号传导效率的受体后增强。目的1将检验MPR通过增加成人LPO中肾内AnglI的产生而导致HTN的假设。SubAims将测试是否：1A）MPR相关的HTN与体内ECV过量有关：1B）MPR导致肾内AnglI过量或激活AnglI生成元件：肾素、血管紧张素原（Aogn）、AnglI转化酶（ACE）;和1C）MPR诱导肾血管对AnglI的收缩反应性增加，通过减少内皮舒张和/或通过增强的受体后信号传导[通过经典的AT 1 R收缩途径与AT 1 R-依赖EGFR反式激活途径]。在非炎症性肾单位缺陷的其他状态下，代偿性单肾单位超滤-旨在维持足够的蛋白质/氮排泄-需要肾内肾素/AnglI（RAS）激活。因此，AIM 2将检验以下假设：相对于肾单位数量减少的体型过大-在快速追赶生长期间发育-诱导成人LPO的血流动力学和RAS异常。子目标将测试预防体型过大（通过热量限制将体重百分位数维持在新生儿水平）是否可预防：2A。HTN/ECV过度/肾单位超滤; 2B.肾内AnglI过量和/或AnglI生成元件的活化;和2C.肾血管对AnglI的反应性增加。目的3将测试的假设，MPR和/或体型过大的影响是由AT 1受体介导的。Subaims将测试体内AT 1 R阻断或安慰剂3A的作用。血流动力学和3B通过经典途径和EGFR反式激活途径（使用新鲜血管/皮质组织中的肾血管反应性和激活与总信号蛋白丰度）对AnglI收缩信号传导的影响。这些研究解决了全球范围内的健康风险，测试了具有潜在临床价值的干预措施（体重控制/AT 1 R阻断），并影响了目前促进低出生体重婴儿追赶性生长的儿科实践。