The overall goal of this research effort is to study the development of the integration of endocrine-cardiovascular relationships. This application focuses on the ontogeny of the renin angiotensin system (RAS) and includes experiments to test three specific hypotheses. The first hypothesis is that the expression of the renin gene in the mammalian kidney increases after 100 days of gestation, peaks in the perinatal period and is accompanied by increases in the concentrations of active and total renin and in the ability of the kidney to secrete active and inactive renin in vivo and in vitro. The second hypothesis is that the prolonged increase in plasma cortisol concentration which occurs in late gestation and peaks in the perinatal period is essential for the increase in renal renin gene expression, for the increase in the renal concentrations of active and total renin and for the increase in the ability of the kidney to secrete renin in vivo and in vitro. The third hypothesis is that a prolonged increase in cortisol in the fetus in early gestation will cause premature maturation of the ability of the fetal kidney to secrete active and inactive renin in vivo and in vitro and will be accompanied by an increase in the relative amount of renal renin messenger RNA, and in the concentrations of active and total renin in the kidney. The chronically cannulated fetal, newborn and adult sheep is the model chosen for study. With this model it is possible to study development of this system in the absence of complications created by the presence of anesthesia and surgical trauma which are inherent in experiments in acutely prepared animals. Moreover, with this model it will be possible to correlate results of physiological experiments in vivo with molecular studies in vitro to increase our understanding of the mechanisms causing developmental alterations in activity in the renin angiotensin system. Increasing our understanding of the maturation of the renin angiotensin system may prove pertinent for the development of new intrauterine therapies, and for the improved management of the premature infant or the term infant in distress. Also, obtaining additional knowledge regarding control elements influencing this system could result in new information useful in understanding certain types of hypertension in infants and adults.
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