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

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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.