Fetal Origins of Adult Hypertension in Microswine

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。在妊娠最后三分之一和哺乳期前两周（肾源期）应用1%母体蛋白限制（MPR）的微型猪后代表现出早期不对称生长迟缓、肾单位数量减少、快速追赶生长和成人高血压（HTN）；单肾元超滤维持正常的全肾功能。成年低蛋白子代（LPO）与正常蛋白子代（NPO）相比表现出关键的肾素/AnglI （RAS）异常：1)肾内AnglI升高，提示AnglI生成增加；2)尽管AT1受体（AT1R）密度降低，但肾微血管对AnglI的收缩反应性增加，提示AT1R受体后收缩信号传导效率增强。目的1将检验MPR通过增加成人LPO的肾内AnglI生成导致HTN的假设。SubAims将测试：1A) mpr相关的HTN是否与体内ECV过量相关；1B) MPR导致肾内AnglI过量或激活AnglI生成元素：肾素、血管紧张素原（Aogn）、AnglI转换酶（ACE）；和1C) MPR通过减少内皮松弛和/或增强受体后信号传导（通过经典的AT1R收缩途径与AT1R依赖性EGFR反激活途径）诱导肾血管对AnglI的收缩反应性增加。在其他非炎症性肾元缺陷状态下，代偿性单肾元超滤——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将验证一个假设，即在快速追赶生长过程中，相对于肾单位数量减少的体型过大，会诱导成人LPO的血流动力学和RAS异常。子目标将测试预防体型过大（通过限制热量来维持新生儿体重百分位数）是否可以预防：2A。HTN/ECV过量/肾元超滤；2 b。肾内AnglI过量和/或活化AnglI生成元素；和2 c。肾血管对AnglI的反应性增加。AIM 3将检验MPR和/或体型过大的影响是由AT1受体介导的假设。子目标将测试体内AT1R阻断剂或安慰剂3a对血液动力学和3B的影响。AnglI收缩信号通过经典途径和egfr转激活途径（利用肾血管反应性和新鲜血管/皮质组织中激活与总信号蛋白丰度）。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/AT1R阻断），并影响了目前促进低出生体重婴儿追赶生长的儿科实践。

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.