The US Food and Drug? Administration recently announced new guidelines for recommended levels of salt intake in our diet. These guidelines highlight the fact that certain individuals are at greater risk for the cardiovascular consequences of a high salt intake. The current proposal seeks to define the mechanisms by which risk factors, such as adiposity and environmental stress, contribute to vascular and renal dysfunction associated with the control of sodium balance. The autcicoid, endothelin (ET)-1, functions through ETA and ETB receptors located in a wide range of cell types. Animal studies have revealed an important role for renal tubular ETB receptors in facilitating sodium excretion. Recent studies from the previous funding period have demonstrated that a high fat diet leads to impairment of ETB receptor dependent natriuresis. Therefore, a major goal of the current project is to determine the mechanisms by which adiposity leads to ETB receptor dysfunction to produce alterations in sodium homeostasis, this includes examining a role for angiotensin II and renal sympathetic nerves. In both human and animal models, investigators in the current PPG have observed that acute stress increases plasma ET-1 concentrations. Investigators in Project 1 demonstrated that acute stress in a subpopulation of subjects results in inappropriate Na excretion for a given level of blood pressure. We have also demonstrated that the blood pressure response to acute stress in the Dahl S rat can be attenuated with a combined ETAlB receptor antagonist, but not a selective ETA antagonist. Thus, we propose to explore the degree to which adiposity and genetic factors contribute to ETB receptor function in humans. These issues will be addressed by four aims, two utilizing the Dahl S model that mimics human salt-sensitivity such as frequently occurs in African Americans, and two aims utilizing human subjects.
Aim 1 will test the hypothesis that angiotensin II and sympathetic nerve activity mediate ETB receptor dysfunction in a model of adiposity/pre-hypertension, the Dahl S rat on a high fat diet.
Aim 2 will test the hypothesis that adiposity results in whole body sodium retention and inflammation that caused by reduced ETB and increased ETA receptor function in the Dahl S rat.
Aim 3 will test the hypothesis that the magnitude of the blood pressure response to acute stress in humans is increased as a result of reduced ETB receptor activity.
Aim 4 will test the hypothesis that obesity is associated with ETB receptor dysfunction in humans due to actions of angiotensin II.

Public Health Relevance

to Public Health: Essential hypertension is the number 1 reason for a physician visit, with 1 in 3 people suffering from the disorder. High dietary salt is a contributing factor in the development of hypertension and our studies seek to identify how why specific individuals do not handle a high salt diet appropriately and develop high blood pressure. This knowledge will enable us to develop more effective prevention and treatment strategies.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Program Project Review Committee (HLBP)
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Georgia Regents University
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De Miguel, Carmen; Speed, Joshua S; Kasztan, Malgorzata et al. (2016) Endothelin-1 and the kidney: new perspectives and recent findings. Curr Opin Nephrol Hypertens 25:35-41
Heimlich, J Brett; Speed, Joshua S; O'Connor, Paul M et al. (2016) Endothelin-1 contributes to the progression of renal injury in sickle cell disease via reactive oxygen species. Br J Pharmacol 173:386-95
Davenport, Anthony P; Hyndman, Kelly A; Dhaun, Neeraj et al. (2016) Endothelin. Pharmacol Rev 68:357-418
Gohar, Eman Y; Giachini, Fernanda R; Pollock, David M et al. (2016) Role of the endothelin system in sexual dimorphism in cardiovascular and renal diseases. Life Sci 159:20-9
Spradley, Frank T; Ho, Dao H; Pollock, Jennifer S (2016) Dahl SS rats demonstrate enhanced aortic perivascular adipose tissue-mediated buffering of vasoconstriction through activation of NOS in the endothelium. Am J Physiol Regul Integr Comp Physiol 310:R286-96
Guan, Zhengrong; Singletary, Sean T; Cha, Haword et al. (2016) Pentosan polysulfate preserves renal microvascular P2X1 receptor reactivity and autoregulatory behavior in DOCA-salt hypertensive rats. Am J Physiol Renal Physiol 310:F456-65
Heimlich, J B; Speed, J S; Bloom, C J et al. (2015) ET-1 increases reactive oxygen species following hypoxia and high-salt diet in the mouse glomerulus. Acta Physiol (Oxf) 213:722-30
Su, Shaoyong; Wang, Xiaoling; Pollock, Jennifer S et al. (2015) Adverse childhood experiences and blood pressure trajectories from childhood to young adulthood: the Georgia stress and Heart study. Circulation 131:1674-81
Speed, Joshua S; Fox, Brandon M; Johnston, Jermaine G et al. (2015) Endothelin and renal ion and water transport. Semin Nephrol 35:137-44
Speed, Joshua S; Pollock, David M (2015) New clues towards solving the mystery of endothelin and blood pressure regulation. Hypertension 66:275-7

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