HL146818-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 changes in the soluble prorenin receptor (sPRR) in the renal proximal tubules which has been linked to upregulation of Na+ transporters that may contribute to salt-sensitivity. Thus, the proposed study will determine the role of sPRR in this patient cohort and in human proximal tubule cells by the candidate. The diversity supplement serves as a robust and comprehensive training plan for the candidate graduate student includes the research plan involving the assessment of the sPRR in term and preterm adults maintained on a high salt diet, the role of Uric Acid on the regulation of sPRR in preterm salt-sensitive patients and the regulation of the sPRR in human proximal tubules and the functional and signaling characteristics of the sPRR. The mentoring team for the candidate is 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. In addition to providing a comprehensive training plain that will ensure a strong foundation and pathway of the candidate to an independent investigator, the proposed research will establish the role of sPRR among individuals born preterm, thus providing evidence for the mechanisms behind the increased risk of hypertension and cardiovascular disease in individuals born prematurely.