Fetal Origins of Adult Hypertension in Microswine

描述(申请人提供)：流行病学研究表明，包括高血压在内的人类心血管疾病与低出生体重有关。1%母体蛋白限制(MPR)在妊娠末期和哺乳期前两周(肾生长期)应用的小型猪后代表现出早期不对称性生长迟缓、肾单位数量减少、快速追赶生长和成人高血压(HTN)，单肾单位超滤维持正常的总肾功能。成年低蛋白后代(LPO)与正常蛋白后代(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，但肾微血管收缩对Angli的反应性增加，提示受体后AT1R收缩信号转导效率增强。目的1验证MPR通过增加成人LPO肾内Angli的生成而导致HTN的假说。SubAims将测试：1A)MPR相关HTN是否与体内ECV过量有关；1B)MPR导致肾内Angli过剩或激活Angli生成元素：肾素、血管紧张素原(Aogn)、Angli转换酶(ACE)；以及1C)MPR通过减少内皮松弛和/或通过增强受体后信号[通过经典的AT1R收缩途径与AT1R依赖的EGFR反式激活途径]诱导肾血管对Angli的收缩反应性增加。在其他非炎症性肾单位缺陷状态下，代偿性单肾单位高滤过--旨在维持足够的蛋白质/氮排泄--需要肾内肾素/血管紧张素转换酶(RAS)的激活。因此，AIM 2将验证这一假设，即在快速追赶生长过程中，相对于肾单位数量减少的身体尺寸过大会导致成年LPO的血流动力学和RAS异常。SubAims将测试预防身体尺寸过大(通过限制卡路里以将身体重量百分位数保持在新生儿水平)是否可以防止：2a。HTN/ECV过度/肾单位超滤；肾内Angli过剩和/或Angli生成元素的激活；和2C。肾血管对Angli的反应性增加。目的3将验证MPR和/或身体尺寸过大的影响是由AT1受体介导的假设。Subaims将测试体内AT1R阻断或安慰剂3A的效果。血流动力学和3B。通过经典和EGFR反式激活途径研究Angli收缩信号(使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)。研究涉及世界范围的健康风险，潜在临床价值的测试干预措施(体重控制/AT1R阻断)，并影响当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.