Fetal Origins of Adult Hypertension in Microswine

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DESCRIPTION (provided by applicant): Human cardiovascular disease, including hypertension, has been linked by epidemiologic studies to low birth weight. Microswine offspring of 1% Maternal Protein Restriction (MPR), applied during last third of gestation plus first two wks of lactation (nephrogenic period), exhibit early asymmetric growth retardation, reduced nephron number, rapid catch-up growth, and adult hypertension (HTN); single-nephron hyperfiltration maintains normal total kidney function. Adult Low-Protein Offspring (LPO) show key Renin/AnglI (RAS) abnormalities vs Normal-Protein Offspring (NPO): 1) elevated intrarenal AnglI, suggesting increased AnglI generation; and 2) increased renal microvascular contractile reactivity to AnglI despite reduced AT1 receptor (AT1R) density, suggesting post-receptor enhancement of AT1R contractile signaling efficiency. Aim 1 will test the hypothesis that MPR leads to HTN via increased generation of intrarenal AnglI in adult LPO. SubAims will test whether: 1A) MPR-related HTN is associated with in vivo ECV excess; 1B) MPR leads to intrarenal AnglI excess or activates AnglI-generating elements: renin, angiotensinogen (Aogn), AnglI Converting Enzyme (ACE); and 1C) MPR induces increased renal vascular contractile reactivity to AnglI, either by reduced endothelial relaxation and/or by enhanced post-receptor signaling [via classic AT1R contractile pathways vs AT1R-dependent EGFR transactivating pathways]. In other states of non-inflammatory nephron deficit, compensatory single-nephron hyperfiltration - designed to maintain adequate protein/nitrogen excretion - requires intrarenal Renin/AnglI (RAS) activation. Thus, AIM 2 will test the hypothesis that Body-Size Excess relative to reduced nephron number - developing during rapid catch-up growth - induces the hemodynamic and RAS abnormalities in adult LPO. SubAims will test whether prevention of body size excess (by caloric restriction to maintain body wt percentile at the neonatal level) prevents: 2A. HTN/ECV excess/nephron hyperfiltration; 2B. intrarenal AnglI excess and/or activation of AnglI-generating elements; and 2C. increased renal vascular reactivity to AnglI. AIM 3 will test the hypothesis that effects of MPR and/or Body-Size Excess are mediated by the AT1 receptor. Subaims will test effects of in vivo AT1R blockade or placebo 3A. on hemodynamic and 3B. on AnglI contractile signaling via classic and EGFR-transactivation routes (using renal vascular reactivity and activated vs total signaling protein abundance in fresh vascular/cortical tissues). Studies address a worldwide health risk, test interventions (weight control/AT1R block) of potential clinical value, and impact the current pediatric practice of promoting catch-up growth in low-birth-wt infants.