Uric Acid, Klotho and Salt Sensitivity in Young Adults Born Preterm

早产青年的尿酸、Klotho 和盐敏感性

• 批准号: 10238939
• 负责人: MARK C CHAPPELL
• 金额: $ 77.47万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10238939
• 关键词: ACE2; Address; Adolescence; Adolescent and Young Adult; Adult; Affect; Allopurinol; Angiotensin II; Angiotensinogen; Attenuated; Autonomic Dysfunction; Baroreflex; Biological Markers; Birth Rate; Blood; Blood Pressure; Blood Vessels; Cardiovascular Diseases; Cause of Death; Cells; Childhood; Clinical; Clinical Trials; Data; Development; Diuresis; Doctor of Philosophy; Epithelial Cells; Event; Exhibits; Frequencies; Functional disorder; Future; Generations; Hour; Human; Hypertension; Impairment; Incidence; Individual; Infant; International; Kidney; Lead; Life; Link; Mediating; Metabolism; Modeling; Monitor; Natriuresis; Neprilysin; Nitric Oxide; Oxidative Stress; Participant; Physiologic pulse; Plasma; Premature Birth; Prevalence; Prevention; Prevention strategy; Production; Proteins; Proximal Kidney Tubules; Renin-Angiotensin System; Research; Research Personnel; Risk; Risk Factors; Role; Serum; Sodium; Sodium Chloride; Sodium-Restricted Diet; System; Testing; Tubular formation; Uric Acid; Urine; Water; angiotensin I (1-7); anti aging; arm; cardiovascular risk factor; cohort; emerging adult; experience; experimental study; fetal; heart rate variability; high risk; human data; improved; indexing; individual response; neuromechanism; novel therapeutics; peer; preclinical study; premature; pressure; prevent; programs; prospective; receptor; renal epithelium; response; salt intake; treatment strategy; urinary; young adult

ABSTRACT Hypertension is the leading risk factor for cardiovascular disease, is highly prevalent with high lifetime cumulative incidence rates, and is the leading cause of death compared to any other risk factor. Premature birth is an emerging and important risk factor for hypertension and cardiovascular disease, as both preterm birth rates and infant survival increase worldwide. Hypertension and cardiovascular disease begin in early adulthood in individuals born prematurely, but the reasons – especially in regard to the role of preterm birth – are unknown. An improved understanding of why hypertension and cardiovascular disease occur in early adulthood in individuals born preterm will enable the development of prevention and treatment strategies to mitigate the burden of cardiovascular disease. Salt sensitivity of blood pressure (SSBP; the change in blood pressure in response to a change in salt intake) is an emerging risk factor for hypertension and cardiovascular disease. However, little is known about the pathophysiology of SSBP, which limits its treatment and prevention. Individuals born preterm may be at higher risk for SSBP, but this too is unknown. Uric acid, which is higher in those born preterm due to altered uric acid metabolism, has been linked to development of SSBP in preclinical studies, but this concept has not been investigated in human trials. Uric acid may lead to SSBP via changes in klotho and the renin-angiotensin system, notably increased angiotensin II and decreased angiotensin-(1-7) in the renal proximal tubules. In individuals born preterm compared to those born at full term, higher uric acid correlates with higher blood pressure, altered renal sodium handling, decreased klotho, increased angiotensin II, and decreased angiotensin-(1-7). Thus, the proposed study will determine the prevalence of SSBP in young adults born preterm versus full-term and will initiate (a) a clinical trial testing the effect of blocking uric acid production with allopurinol on SSBP, and (b) a mechanistic study evaluating uric acid's effects on the renin- angiotensin system and klotho in human renal proximal tubule cells. We hypothesize that (i) more young adults with SSBP will have been born preterm versus full-term; (ii) mitigation of uric acid levels will reduce the proportion of young adults born preterm with SSBP, vascular stiffness, and autonomic dysfunction; and (iii) uric acid will promote oxidative stress within human proximal tubule cells, resulting greater angiotensin II relative to angiotensin-(1-7) and diminished klotho. Our team is co-led by experienced and senior investigators with extensive experience in the preterm and term cohort, the influence of programing events on hypertension and internationally recognized expertise in the renin-angiotensin system and renal models of hypertensive disease. Our results will establish the role of uric acid in SSBP among individuals born preterm, thus providing evidence for the mechanisms behind the increased risk of hypertension and cardiovascular disease in individuals born prematurely.

抽象的 高血压是心血管疾病的主要危险因素，寿命高很普遍 与任何其他危险因素相比，累积事件率是死亡的主要原因。早产 出生是高血压和心血管疾病的新兴而重要的危险因素，因为两个早产 生日率和婴儿生存率在全球范围内增加。高血压和心血管疾病从早期开始 过早出生的个人成年，但原因 - 尤其是关于早产的作用 - 是未知的。对为什么高血压和心血管疾病发生的原因有了改进的了解 出生早产的人的成年将使预防和治疗策略的发展得以发展 减轻心血管疾病的燃烧。血压的盐敏感性（SSBP；血液变化 响应盐分变化的压力）是高血压和心血管的新兴危险因素 疾病。但是，对SSBP的病理生理学知之甚少，SSBP限制了其治疗和预防。 SSBP出生的人可能面临更高的风险，但这也是未知的。尿酸，尿酸更高 那些由于尿酸代谢改变而出生的那些早产，与临床前的SSBP的发展有关 研究，但是这个概念尚未在人类试验中进行研究。尿酸可能会通过变化导致SSBP Klotho和肾素 - 血管紧张素系统，特别是增加血管紧张素II并改善血管紧张素 - （1-7） 肾近端管。与全学期出生的人相比，出生早产的人，尿酸较高 与较高的血压相关，肾脏钠处理的改变，klotho降低，血管紧张素增加 II，并改善血管紧张素 - （1-7）。这是拟议的研究将确定SSBP年轻人的患病率 成年人出生的早产与成熟，将启动（a）临床试验测试阻断尿酸的作用 在SSBP上使用别嘌醇的生产，以及（b）评估尿酸对肾素的影响的机械研究 人类肾近端细胞细胞中的血管紧张素系统和klotho。我们假设（i）更多的年轻人 与SSBP有关，将是早产与完整学期的诞生； （ii）缓解尿酸水平将减少 患有SSBP的早产年轻人的比例，血管僵硬和自主功能障碍； （iii）尿 酸会促进人近端小管细胞内的氧化应激，从而导致更大的血管紧张素II相对于 血管紧张素 - （1-7）并减少了Klotho。我们的团队由经验丰富的高级调查员共同领导 在早产和术语队列中的丰富经验，编程事件对高血压和 国际公认的肾素 - 血管紧张素系统和高血压疾病肾模型的专业知识。 我们的结果将确定尿酸在SSBP中的作用 对于出生的个体高血压和心血管疾病风险增加的机制 过早。