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

摘要 高血压是心血管疾病的主要危险因素，患病率高，寿命长 累积发病率，并且与任何其他风险因素相比是死亡的主要原因。过早 分娩是高血压和心血管疾病的一个新的重要危险因素， 世界各地的出生率和婴儿存活率都在提高。高血压和心血管疾病开始于 早产儿的成年期，但原因-特别是在早产的作用方面- 是未知的。提高对高血压和心血管疾病发生在早期的理解 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。血压的盐敏感性（SSBP;血液中 盐摄入量的变化引起的压力）是高血压和心血管疾病的一个新的危险因素 疾病然而，对SSBP的病理生理学知之甚少，这限制了其治疗和预防。 早产的个体可能有较高的SSBP风险，但这也是未知的。尿酸，这是较高的， 那些由于尿酸代谢改变而早产的人，已经与临床前SSBP的发展有关。 研究，但这个概念尚未在人体试验中进行研究。尿酸可能通过改变 klotho和肾素-血管紧张素系统，显着增加血管紧张素II和降低血管紧张素-（1-7）， 肾近端小管与足月出生的人相比，早产的人尿酸较高， 与血压升高、肾钠处理改变、klotho降低、血管紧张素升高相关 Ⅱ，降低血管紧张素-（1-7）。因此，拟议的研究将确定SSBP在年轻人中的患病率。 早产与足月的成年人，并将启动（a）一项临床试验，测试阻断尿酸的效果 （B）评估尿酸对SSBP的肾素-血管紧张素转换酶的影响的机制研究。 血管紧张素系统和klotho在人肾近曲小管细胞中的表达。我们假设（i）更多的年轻人 与足月相比，患有SSBP的婴儿将早产;（ii）尿酸水平的缓解将减少 早产的年轻人患有SSBP、血管僵硬和自主神经功能障碍的比例;和（iii）尿 酸将促进人近端小管细胞内的氧化应激，导致相对于人近端小管细胞更大的血管紧张素II。 血管紧张素-（1-7）和klotho减少。我们的团队由经验丰富的资深调查人员共同领导， 在早产儿和足月儿队列中的丰富经验，程控事件对高血压的影响， 国际公认的专业知识，在肾素-血管紧张素系统和肾脏模型的高血压疾病。 我们的研究结果将建立尿酸在早产儿SSBP中的作用，从而为早产儿SSBP的发生提供证据。 高血压和心血管疾病风险增加背后的机制， 过早地。

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.