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: 10460255
• 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/10460255
• 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; blood pressure elevation; 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 response; 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，其患病率很高，寿命较长 累积发病率，与任何其他危险因素相比，是导致过早死亡的主要原因。 出生是高血压和心血管疾病的一个新兴的重要危险因素，因为早产 全世界的出生率和婴儿存活率均有所提高，高血压和心血管疾病很早就开始出现。 早产个体的成年期，但其原因——尤其是早产的作用—— 目前尚不清楚为什么高血压和心血管疾病会在早期发生。 早产儿的成年期将有助于制定预防和治疗策略 减轻心血管疾病的负担。血压盐敏感性（SSBP；血液变化） 盐摄入量变化引起的压力）是高血压和心血管疾病的一个新兴危险因素 然而，人们对 SSBP 的病理生理学知之甚少，这限制了其治疗和预防。 早产儿患 SSBP 的风险可能较高，但这也是未知的，尿酸水平较高。 那些由于尿酸代谢改变而早产的人，在临床前研究中已与 SSBP 的发生有关 研究，但这一概念尚未在人体试验中得到研究，尿酸可能通过改变而导致 SSBP。 klotho 和肾素-血管紧张素系统，显着增加血管紧张素 II 和减少血管紧张素-(1-7) 与足月出生的人相比，早产儿的肾近端小管的尿酸较高。 与高血压、肾钠处理改变、克洛索减少、血管紧张素增加相关 II，血管紧张素-(1-7) 降低因此，拟议的研究将确定年轻人中 SSBP 的患病率。 早产与足月出生的成年人将启动 (a) 一项临床试验，测试阻断尿酸的效果 别嘌呤醇对 SSBP 的产生，以及（b）评估尿酸对肾素的影响的机制研究 人肾近曲小管细胞中的血管紧张素系统和 klotho 我们努力（i）更多的年轻人。 患有 SSBP 的婴儿会早产或足月出生；(ii) 尿酸水平的降低会降低 患有 SSBP、血管僵硬和自主神经功能障碍的早产青年比例；以及 (iii) 尿酸； 酸会促进人近曲小管细胞内的氧化应激，导致血管紧张素 II 相对于 血管紧张素-(1-7) 和减少的 klotho 我们的团队由经验丰富的高级研究人员共同领导。 在早产儿和足月队列、编程事件对高血压的影响和 在肾素-血管紧张素系统和高血压肾模型方面具有国际公认的专业知识。 我们的结果将确定尿酸在早产儿 SSBP 中的作用，从而提供证据 出生时高血压和心血管疾病风险增加的机制 过早地。