Antenatal Steroids Exposure and Adipose Tissue Renin-Angiotensin-System Function

产前类固醇暴露与脂肪组织肾素血管紧张素系统功能

• 批准号: 8381682
• 负责人: JAMES C. ROSE
• 金额: $ 19.52万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-20 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8381682
• 关键词: Address; Adipose tissue; Adrenal Cortex Hormones; Adult; Animal Model; Animals; Birth; Blood Pressure; Cardiovascular Diseases; Cardiovascular system; Development; Diet; Environment; Epidemiology; Equilibrium; Event; Exhibits; Fatty acid glycerol esters; Glucocorticoids; Glucose; Homeostasis; Human; Hypertension; Impairment; Incidence; Individual; Inflammation Mediators; Instruction; Insulin; Insulin Resistance; Kidney; Mediating; Metabolic; Nephrons; Newborn Infant; Nutritional; Obesity; Pathway interactions; Pregnancy; Rattus; Renin-Angiotensin System; Risk; Risk Factors; Role; Ruminants; Sheep; Steroids; System; Testing; Work; blood pressure regulation; diabetic; feeding; fetal programming; glucose tolerance; human subject; modifiable risk; novel; offspring; postnatal; premature; prenatal; prenatal exposure; programs; respiratory distress syndrome; sex; subcutaneous; young adult

The mechanism by which glucocorticoids program the cardiometabolic impairment is not completely understood. Although one final common pathway may involve the kidney, the decrease in nephron number, by itself, does not explain the elevation in blood pressure. In this project we will address an additional mechanism by which prenatal steroids cause cardiometabolic impairment, i.e., a functional alterafion in the local adipose tissue renin angiotensin system (RAS) and that these alterafions are amplified by obesity, a "second hit" that tilts the balance towards insulin resistance and further elevations in blood pressure. The working hypothesis is that antenatal steroid exposure has a "programming effect" on white adipose tissue development and funcfion and predisposes the individual for developing insulin resistance and hypertension. We further hypothesize that 1) antenatal steroid exposure alters the function of a local renin-angiotensin system (RAS) within the white adipose tissue, 2) the abnormal adipose tissue RAS function predisposes the individual for developing cardiovascular and metabolic alterations, 3) Obesity exaggerates the functional derangement of adipose tissue, thus increasing the impact antenatal steroid exposure has on cardiovascular and metabolic regulafion. Obesity will be induced using a standard ruminant formula, thus fat composifion of the diet is removed as a confounding factor. Sheep of both sexes will be randomly allocated to be fed 100% of recommended nutritional allowance or ad libitum for three months. Given the increasing incidence of obesity and the mounting evidence for a developmental origin of cardiovascular disease, the studies proposed will determine if obesity, a modifiable risk factor, has a significant contribution in the development of cardiovascular diseases in animals exposed antenatally to steroids. We will test these hypotheses with the following specific aims: Specific Aim 1: To study the effects of antenatal glucocorticoid exposure on the expression of critical components of the RAS and inflammatory mediators in white adipose fissue depots (subcutaneous, omental and perirenal) and the consequences these changes have on adipose fissue function. Specific Aim 2: To determine which component(s) of the adipose tissue RAS mediate(s) the cardiometabolic dysregulafion in animals exposed antenatally to glucocorticoids. Specific Aim 3: To study the mechanism by which superimposed obesity exaggerates the cardiovascular and metabolic abnormalities induced by antenatal steroid exposure. RELEVANCE (See Instructions): Antenatal glucocorticoids remain the single alternative to reduce the risk of respiratory distress syndrome in premature newborns. Considering the functional upregulafion of the RAS system in steroid-treated animals and the role of the RAS in the regulation of blood pressure in obese and diabetic humans, results from this proposal will pave the way for establishing if obesity in adulthood magnifies the alterations already present in animals exposed prenatally to glucocorticoids.

糖皮质激素调节心脏代谢损伤的机制尚不完全清楚 明白了。虽然最后一个共同途径可能涉及肾脏，但肾单位数量减少， 其本身并不能解释血压升高。在这个项目中，我们将解决一个额外的问题 产前类固醇导致心脏代谢损伤的机制，即心脏代谢功能改变 局部脂肪组织肾素血管紧张素系统（RAS），并且这些改变会因肥胖而放大， “第二次打击”使平衡向胰岛素抵抗和血压进一步升高倾斜。这 工作假设是产前类固醇暴露对白色脂肪组织有“编程效应” 发育和功能并使个体易患胰岛素抵抗和高血压。 我们进一步假设 1) 产前类固醇暴露改变了局部肾素-血管紧张素的功能 白色脂肪组织内的 RAS 系统，2）异常的脂肪组织 RAS 功能容易导致 个体发生心血管和代谢改变，3) 肥胖夸大了功能 脂肪组织紊乱，从而增加产前类固醇暴露对心血管的影响 和代谢调节。使用标准反刍动物配方诱导肥胖，因此脂肪成分 饮食作为一个混杂因素被删除。雌雄羊随机分配，饲喂率100% 推荐的营养摄入量或任意摄入三个月。鉴于发病率不断增加 肥胖和心血管疾病的发育起源的越来越多的证据，研究 提议将确定肥胖这一可改变的危险因素是否对发育有重大贡献 产前接触类固醇的动物的心血管疾病。我们将测试这些假设 具体目标如下： 具体目标 1：研究产前糖皮质激素暴露对关键表达的影响 白色脂肪组织库（皮下、网膜）中 RAS 的成分和炎症介质 和肾周）以及这些变化对脂肪组织功能的影响。 具体目标 2：确定脂肪组织 RAS 的哪些成分介导 产前接触糖皮质激素的动物心脏代谢失调。 具体目标3：研究叠加肥胖加剧心血管疾病的机制 以及产前类固醇暴露引起的代谢异常。 相关性（参见说明）： 产前糖皮质激素仍然是降低呼吸窘迫综合征风险的单一替代方案 早产儿。考虑类固醇治疗动物 RAS 系统的功能上调 以及 RAS 在肥胖和糖尿病患者血压调节中的作用，由此得出 该提案将为确定成年期肥胖是否会放大已经存在的变化铺平道路 产前接触糖皮质激素的动物。