Fetal origins of adult hypertension in microswine

越来越多的人类流行病学证据将胎儿宫内发育迟缓(IUGR)和成人“X综合征”联系在一起：高血压、肥胖、糖尿病、冠状动脉粥样硬化和肾功能衰竭的风险。在小型猪的初步研究中，在肾脏发生期间(最后1/3孕期+出生后3周)母体等卡路里蛋白限制(0.5%对14%)可在3周时产生IUGR，快速追赶生长至对照体重(超重)的123%，成人高血压，组织学肾单位数量减少，肾小球滤过率正常，提示单肾单位高滤。在低蛋白母猪3周和6个月大的后代中，肾脏皮质AT1和AT2受体定量放射自显影都是异常的，但以独特的方式出现。我们假设，过度的食欲/身体形象大小会为数量较少的肾单位产生过量的蛋白质负荷，推动肾素/血管紧张素转换酶(RAS)的持续激活，通过单肾单位超滤实现氮平衡。这种RAS反应预计会放大钠滞留和细胞外液体容量(ECV)过多，而肾单位较少，从而导致高血压。在母猪蛋白质限制/IUGR的小型猪模型中，对子代的研究将解决：1)IUGR是否改变了关键发育阶段(早产；出生后2周；高血压前期3个月；成年6个月)循环与肾内RAS的激活状态，包括正常饮食低蛋白与正常蛋白子代相比，肾素、血管紧张素原、ACE、AngII和AT1/AT2受体的mRNA、蛋白和活性水平；2)IUGR是否增强出生后血压(BP)、ECV、Na平衡以及体内循环与肾内RAS组分对饮食干预Angii阻滞剂的动态平衡反应；3)IUGR是否在体外增强培养的血管平滑肌AT1信号的效力；4)IUGR子代将成年体重限制在正常蛋白质对照组的75%是否会减弱成年BP、体脂质量、ECV和肾内RAS组分。这一结果与高血压的病因机制以及对暴露于IUGR的成年心血管和肾脏疾病风险儿童的预防管理有关。

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.