Impaired stress-induced pressure natriuresis is defined as an increase in blood pressure (BP) during a period of extended stress without an adequate compensatory increase in urinary sodium excretion (UNaV) to contribute to the return of systolic BP (SBP) to pre-stress levels. Studies on animal models and human subjects reveal that BP increase under stress depends significantly on interleukin-6 (IL-6). IL-6 is a multi- functional cytokine that acts through a receptor comprising two subunits, IL-6 receptor (IL-6R) and gp130 cytokine signal transducer (gp130), and releases C-reactive protein (CRP). The main goal thus is to determine the role of the IL-6 pathway on the dynamic regulation of sodium homeostasis and BP under stress in normotensive youth. To achieve this goal, this proposed study will take two approaches: comprehensive analyses of genetic variability and measurements of circulating levels. Therefore, the specific aims are to test the following hypotheses: 1. Youth with unfavorable genotypes or haplotypes of the genes in the IL-6 pathway compared to those without will show a reduced stress-induced increase in UNaV and delayed SBP recovery following stress. 2. Plasma IL-6 and CRP levels in response to stress will be inversely related to stress-induced UNaV in youth, but positively related to recovery SBP following stress in youth. A total of 500 subjects aged 15-19 yrs will be studied which include an equal number of whites and blacks, boys and girls. All subjects have been previously tested with an extended stress protocol including a recovery period. Single nucleotide polymorphisms (SNPs) in the IL-6 and CRP genes will be systematically examined in these subjects using tagging SNP and haplotype approaches. Functional SNPs of the IL-6, IL6R, gp130 and CRP genes will also be studied. Buccal cell DNA from the parents of these youth will be collected to facilitate (1) haplotype reconstruction and analyses and (2) transmission disequilibrium tests (TDTs). Plasma levels of IL-6 and CRP will be examined in a subsample of 109 subjects. This research will provide novel insight into the interactions between stress, inflammation, and genetics, and their contribution to the pathogenesis of essential hypertension. The project aims to investigate the influence of inflammation, stress and genes on the body's ability to release sodium. Understanding the connections between stress, inflammation, and genes will provide a fresh approach into evaluating risk factors for high blood pressure. ? ? ?
