Fetal origins of adult hypertension in microswine

小型猪成年高血压的胎儿起源

• 批准号: 6595218
• 负责人: Susan P Bagby
• 金额: $ 31.28万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6595218
• 关键词: angiotensin II; appetite; autoradiography; biological signal transduction; body weight; caloric dietary content; cardiovascular disorder risk; dietary proteins; dietary restriction; dietary sodium; disease /disorder proneness /risk; growth /development; hemodynamics; high performance liquid chromatography; histogenesis; hypertension; kidney disorder; mother /embryo /fetus nutrition; nephrogenesis; pathologic process; prenatal growth disorder; radioimmunoassay; renal tubule; renin; renin angiotensin system; swine; tissue /cell culture; vascular smooth muscle

A growing body of human epidemiologic evidence links intrauterine growth retardation (IUGR) and adult "Syndrome X": hypertension, obesity, diabetes, coronary artherosclerosis, and risk of renal failure. In preliminary studies in microswine, maternal isocaloric protein restriction (0.5% vs. 14%) during nephrogenesis (last 1/3 gestation +3 weeks post- natally) yields IUGR at 3 weeks, rapid catch-up growth to 123% of control body weight (overweight), adult hypertension, reduced nephron number by histology, and normal GFR suggesting single-nephron hyperfiltration. Renal cortical AT1 and AT2 receptors by quantitative autoradiography are abnormal in both 3-week and 6-month old offspring of low-protein sows but in unique ways. We hypothesize that excess appetite/body image size generate excess protein load for the low number of nephrons, driving sustained intrarenal renin/AngII (RAS) activation to achieve nitrogen balance via single-nephron hyperfiltration. This RAS response is predicted to amplify the Na retention and extracellular fluid volume (ECV) excess expected with fewer nephrons, yielding hypertension. In a microswine model of maternal protein restriction/IUGR, studies in offspring will address: 1) whether IUGR modifies the activation state of circulating vs. intrarenal RAS at key developmental stages (preterm; 2-weeks postnatal; 3-month pre- hypertensive juvenile; and 6-month adult), including mRNA, protein, and activity levels for renin, angiotensinogen, ACE, AngII, and AT1/AT2 receptors at Low-Protein vs. Normal-protein offspring on ad lib normal diet; 2) whether IUGR enhances postnatal homeostatic responses of blood pressure (BP), ECV, Na balance, and circulating vs. intrarenal RAS components in vivo to dietary sodium manipulation to AngII blockade; 3) whether IUGR amplifies AT1 signaling efficacy in vitro in cultured vascular smooth muscle at each developmental stage; and 4) whether global caloric restriction to limit adult bodyweight to 75% of Normal-protein controls in IUGR offspring attenuates adult BP, body fat mass, ECV, and intrarenal RAS components. Results are relevant to etiologic mechanisms of hypertension and to the preventive management of IUGR-exposed children at risk for adult cardiovascular and renal disease.

越来越多的人类流行病学证据将宫内发育迟缓（IUGR）与成人“X综合征”（高血压、肥胖、糖尿病、冠状动脉粥样硬化和肾衰竭风险）联系起来。在小型猪的初步研究中，肾发生期间（妊娠最后1/3+出生后3周）母体等热量蛋白限制（0.5% vs 14%）导致3周时IUGR，快速追赶生长至对照体重的123%（超重），成年高血压，组织学肾单位数量减少，GFR正常，表明单肾单位超滤。 肾皮质AT 1和AT 2受体的定量放射自显影是异常的，在3周龄和6月龄的后代低蛋白母猪，但在独特的方式。我们假设过度的食欲/身体形象尺寸会为少量的肾单位产生过量的蛋白质负荷，从而驱动持续的肾内肾素/血管紧张素II（RAS）激活，以通过单肾单位超滤实现氮平衡。预计这种RAS反应会放大Na潴留和细胞外液体积（ECV）过量，预计肾单位较少，导致高血压。在母体蛋白限制/IUGR的微型猪模型中，后代研究将解决：1）IUGR是否在关键发育阶段改变循环与肾内RAS的激活状态（早产儿;出生后2周; 3个月高血压前期青少年;和6个月的成人），包括mRNA，蛋白质和活性水平的肾素，血管紧张素原，ACE，血管紧张素II，（2）IUGR是否增强了出生后血压（BP）、ECV、Na平衡和体内循环与肾内RAS组分对饮食钠调控对AngII阻断的稳态反应; 3）IUGR是否在每个发育阶段在体外培养的血管平滑肌中放大AT 1信号传导功效;以及4）在IUGR后代中将成人体重限制为正常蛋白质对照的75%的总体热量限制是否减弱成人BP、体脂量、ECV和肾内RAS组分。结果与高血压的病因机制和IUGR暴露儿童成人心血管和肾脏疾病的风险的预防管理。