The overall objective of this research is to test our hypothesis that renal tubular phosphate (Pi) transport in the fetus is different from the adult of the species and the difference is in the intrinsic Pi transport system in the lumenal brush border membrane, either in quantity of the transporter or in transporter properties. Preliminary in vivo studies in fetal lambs showed that urine Pi excretion is negligible and that there is relative (to adults) hyperphosphatemia as is true throughout growth. However, the fetal kidney responds to parathyroid hormone (PTH) and other stimuli with changes in Pi clearance. A TmPi was not demonstrated in the fetal kidney and TmPi in postnatal life is higher during growth than in the adult. Specific mechanisms responsible for more avid renal tubular Pi reabsorption in the young are not known. Preliminary studies measuring Pi uptake in vitro in fetal lamb renal brush border membrane vesicles (BBMV) showed a similar Km but a higher Vmax for Na+ gradient-dependent Pi uptake compared to the pregnant ewe. Additionally, Na+ gradient Pi uptake in the fetus was greater at acidic pH rather than at alkaline pH as in adult animals and initial K+ stimulated Pi uptake was approximately 51% of Na+-Pi uptake whereas it is negligible in the adult. Preliminary correlation of thermotropic phase transition of brush border membranes showed greater lipid fluidity in the fetal kidney compared to the ewe.
The specific aim of this research is to investigate maturational changes in cellular mechanisms for Na+ and non-Na+ stimulated Pi uptake in BBMV from fetal lambs, pregnant ewes and non-pregnant adult sheep. Studies will include kinetic analysis, effect of membrane diffusion potential, substrate specificity and affinity, cation stimulation, role of pH, alkaline phosphatase and membrane permeability. In acute as well as chronic studies, renal Pi clearance in vivo and Pi uptake in vitro will be studied simultaneously. Pertubations will include fetal thyro-parathyroidectomy, Pi depletion, lactic and/or NH4Cl acidosis and infusion of Pi, vitamin D and PTH. The significance of this research is that it will be the first to investigate celllular mechanisms involved in renal Pi reabsorption in utero. The results will provide new and significant insight into understanding maturation of cellular mechanisms for renal tubular Pi transport.
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