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，非常普遍，寿命长。 累积发病率，与任何其他危险因素相比，是导致死亡的首要原因。过早 出生是高血压和心血管疾病的一个新出现的重要危险因素，因为两者都是早产 世界范围内的出生率和婴儿存活率都在上升。高血压和心血管疾病在早期就开始了 早产个体的成年期，但原因--特别是关于早产的作用-- 都是未知的。提高对高血压和心血管疾病发生在早期的原因的理解 早产儿的成年期将使预防和治疗战略的制定成为可能 减轻心血管疾病负担。血压盐敏感性(SSBP；血液中的变化 对盐摄入量变化的反应压力)是高血压和心血管疾病的新危险因素 疾病。然而，对SSBP的病理生理机制知之甚少，限制了其治疗和预防。 早产儿患SSBP的风险可能更高，但这一点也是未知的。尿酸，其含量较高 那些由于尿酸代谢改变而早产的人，与临床前SSBP的发生有关 研究，但这一概念还没有在人体试验中进行研究。尿酸可能通过以下变化导致SSBP Klotho和肾素-血管紧张素系统显著增加血管紧张素II和降低血管紧张素-(1-7)。 肾近端小管。早产儿与足月儿相比，尿酸更高 与血压升高、肾脏钠处理改变、血钾降低、血管紧张素升高有关 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 成人早产与足月出生相比，将启动(A)一项临床试验，测试阻断尿酸的效果 和(B)一项评估尿酸对肾素的影响的机制研究。 人肾近端小管细胞的血管紧张素系统与血管紧张素转换酶。我们假设(I)更多的年轻人 患有SSBP的人将早产而不是足月出生；(Ii)尿酸水平的降低将减少 早产儿患有SSBP、血管僵硬和自主神经功能障碍的比例；以及(Iii)尿液 酸将促进人近端小管细胞内的氧化应激，导致更大的血管紧张素II 血管紧张素-(1-7)和降低Klotho。我们的团队由经验丰富的高级调查人员共同领导， 在早产儿和足月儿队列、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病肾脏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 关于出生时高血压和心血管疾病风险增加背后的机制 为时过早。

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.