Prenatal and Perinatal Programming of Adult Hypertension

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DESCRIPTION (provided by applicant): Low birth weight is a risk factor for the development of human essential hypertension. The goal of the project is to define the mechanisms by which prenatal and perinatal factors program later hypertension. An experimental rat model of adult hypertension associated with low birth weight has been validated by preliminary experiments and will be used for all studies. The hypothesis is that pre- and perinatal hormonal imprinting irreversibly alters the sodium handling characteristic of the maturing kidney, resulting in sodium retention, expansion of extracellular volume (ECV), and hypertension. The studies will focus on the renal renin-angiotensin system (RAS) and the cortical collecting duct (CCD) which are critical regulators of sodium balance. The following potential mechanisms will be investigated: ECV will be measured to test the hypothesis that it is expanded during the development of hypertension. Persisting upregulation of intrarenal RAS and failure to regress normally after birth would lead to sodium retention. This will be examined by determining the intrarenal expression of the RAS components at different time points before and after the development of hypertension by molecular biology methods; renal and systemic angiotensin I and angiotensin II contents will also be measured. CCD sodium transport is hypothesized to be upregulated due to prenatal imprinting of the angiotensin II type 1 receptor, the 11-beta-hydroxysteroid dehydrogenase enzyme, and/or the mineralocorticoid receptor in this nephron segment. Isolated CCDs will be used to study the sodium transport rate and the expression of the specific genes and proteins involved in the Na transport pathway. To assess the contribution of reduced Na filtration to the development of hypertension, total nephron number as well as whole kidney and single nephron filtration rate will be measured; also, the total nephron number will be manipulated using prenatal retinoic acid treatment. Based on preliminary experiments, the hypothesis that the development of prenatally programmed hypertension can be modified or prevented during a postnatal window will be tested. The effect of short-term postnatal dietary and phamacological manipulations on the long-term blood pressure profile will be investigated.