Renal Control of Body Fluid Volume and Circulatory Dynamics

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The kidneys play a central role in long-term regulation of extracellular fluid volume and arterial pressure. A common defect that has been found in all forms of hypertension examined to date is a hypertensive shift in the pressure natriuresis relationship. During the previous project period, studies from our laboratories determined the physiological mechanisms whereby endothelial-derived factors and neurohormonal systems alter renal-pressure natriuresis and blood pressure regulation in a rat model of pregnancy-induced hypertension (PIH), produced by chronic reductions in uterine perfusion pressure. In this proposal, a major objective is to define the interaction between endothelin, oxidative stress and tumor necrosis factor in mediating the altered renal-pressure natriuresis and hypertension in response to chronic reductions in uterine perfusion pressure in pregnant rats. The central hypothesis to be tested in this proposal is that a reduction in uteroplacental perfusion pressure causes hypertension by reducing renal-pressure natriuresis. The reduction in pressure natriuresis occurs as a result of placental and or leukocyte-derived cytokines causing endothelial cell activation that leads to enhanced formation of reactive oxygen species via endothelin, angiotensin II and cytokine-dependent mechanisms. These abnormalities reduce renal plasma flow and glomerular filtration thereby decreasing renal sodium excretory function. To test this hypothesis, arterial pressure, renal, hormonal, and endothelial function will be examined in a conscious, chronically-instrumented rat model of chronic PIH produced by long-term reductions in uterine perfusion pressure (RUPP). Data obtained in this model during the previous grant period indicate that the hypertension produced by decreased perfusion pressure to the uteroplacental unit is associated with proteinuria, significant reductions in renal plasma flow and GFR, a hypertensive shift in the pressure natriuresis relationship, cytokine activation, and endothelial dysfunction. Specific aims to be addressed are: 1) To test the hypothesis that abnormalities in cardiovascular and renal function during chronic reductions in uteroplacental perfusion pressure are due to elevations in maternal plasma TNF alpha 2) To test the hypothesis that endothelin plays an important role in mediating TNF alpha-induced abnormalities in cardiovascular and renal function in pregnant rats 3) To test the hypothesis that estrogens and or progesterone enhance the endothelial activation and hypertensive response to TNF alpha 4) To test the hypothesis that reactive oxygen species mediate abnormalities in cardiovascular and renal function during chronic reductions in uteroplacental perfusion pressure.