Evidence in the epidemiological literature indicates that factors in the intrauterine and early extrauterine environment that affect early growth patterns, and that are most likely related to maternal nutrition, cause adaptations in the offspring that set a trajectory leading to increased risk for cardiovascular disease in adulthood. Experimental evidence in the rat indicates that a restricted maternal dietary protein intake during pregnancy leads to fewer and less well-developed nephrons in the newborns, as well as hypertension in the adult offspring. The renin-angiotensin system (RAS) is known to play an important role in normal renal development. The overarching hypothesis of this application is that changes in maternal protein intake alter the normal pattern of changing RAS activity and renal development in the fetus and newborn, and that this early """"""""programining"""""""" sets a trajectory leading to increased risk for cardiovascular disease later in life. Specifically, in pregnant rats maintained on different levels of protein intake, and their offspring the following hypotheses will be tested: 1) that the circulating and/or intrarenal RAS is altered in fetal and newborn rats whose mothers were protein-restricted during pregnancy, 2) that maternal protein restriction leads to reduced nephron number in the offspring which is associated with hypertension and alterations in renal function, and that these pathophysiologic changes are due to the reduced nephron number and normal associated changes in functional capability per se, 3) that the critical time during development for this diet-sensitive """"""""programming"""""""" of future blood pressure setpoint coincides with the period of nephrogenesis, and 4) that maintenance of the offspring on a low protein diet throughout life will prevent or attenuate the developement of hypertension and associated post-devepomental renal pathophysiological changes. Measurements of RAS components in plasma and tissue of rat fetuses and newborns will be done using radioimmunoassays, Northern blotting immunohistochemistry, and in situ hybridization. Juvenile and adult offspring will be chronically instrumented for measurements of arterial pressure and renal function.
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