The goal of this study is to establish the degree to which decreased fetal nutrient availability has duration of exposure and gender-specific affects on the fetal baboon kidney. Significance: The American Kidney Foundation estimates 20 million Americans (1 in 9 adults) suffer from chronic renal disease (CRD); by 2020 the estimate reaches 1 in 4. There are an increasing number of epidemiologic and animal reports that show range of maternal perturbations including maternal nutrient restriction (MNR) in pregnancy that impair fetal renal development, suggesting an in utero component of predisposition to CRD. Preliminary data: Our baboon model at 0.5 of gestation (G) shows that a 30% decrease in maternal global nutrition from 0.16 to 0.5 G (i) decreases proximal tubule density while decreasing mRNA expression of fetal renal extracellular matrix components fibronectin, laminin, collagen IV, integrin-linked kinase, matrix metalloproteinase 2 and TGF/?; (ii) decreases mRNA expression of fetal renal growth factors IGF, VEGF, EGF receptor (R) and PDGFR; and (iii) alters components of the fetal renal renin-angiotensin system (RAS) in a fetal gender-specific manner. Similarities in nutrition, placentation and kidney development between the baboon and humans make this model a unique opportunity for significant primate studies of gene/environment interaction that are not possible in humans. Hypothesis: MNR has duration of exposure and gender specific effects on fetal baboon kidney development that are primarily mediated by decreased extracellular matrix components expression, growth factor expression, cytokine expression and decreased nutrient sensing pathway activity. Reduced fetal nutrient availability [1] decreases nephron length, decreases glomerular endowment and increases glomerular size at term; [2] decreases expression of growth factors involved in vasculogenesis and angiogenesis resulting in decreased peritubular and glomerular capillary density; and [3] impacts the intra- renal renin-angiotensin system in a gender specific manner by increasing intra-renal 11/MHSD1 and aromatase activity. Approach: Studies will be conducted on fresh, frozen and fixed fetal kidney at 0.33, 0.50, 0.66 and 0.90 G using: (i) histology and unbiased stereology; (ii)QRT-PCR/ISH and Western blot/IHC for mRNA and protein expression and localization; (iii) mobility band shift assay for gene transcriptional regulation; and (iv) growth factor activity assay in explants in Matrigel culture and isolated proximal tubule cell 3D culture. Synergy: All three projects study the effects of MNR on the fetal baboon as mediated, at least in part, by the IGF system peptides. Lay Description: We pass more biological milestones before we are born than at any other time in life. Our data will develop what is know about kidney development in the primate and demonstrate that sub-optimal conditions in utero alter the trajectory of renal development. Clinicians will use the information to understand optimal life style and diet in pregnancy.
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