Intrinsic to the process of growth is the maintenance of a positive balance for a variety of substances, including Pi. Work performed in our laboratories has demonstrated that the rate of tubular reabsorption of Pi per gram of kidney weight is almost four fold higher in the newborn than in an adult animal at comparable filtered loads. A high extra to the intracellular concentration gradient of Pi in the presence of a high permeability of the tubular luminal memhbrane, rather than differences in kinetics of the Na+-Pi carrier, appear to account for the enhanced renal reabsorption of Pi observed in the growing subject. We are speculating that the process of growth per se and the attendant high turnover rate of phosphate-containing high-energy yielding products account for the low intracellular concentration of Pi. The experiments included in the current application are designed to test the hypothesis that the low intracellular concentration of Pi is indeed the major factor responsible for the enhanced transepithelial movement of Pi during development. To this end, newborn and adult animals will be subjected to high and low phosphate diets in order to modify the intracellular concentration of Pi. Additional maneuvers, such as administration of substances known to interfere with the deposition of new bone, or the synthesis of protein will be used in an attempt to determine the relationship between growth and intracellular metabolism, on one hand, and that between intracellular metabolism and renal transport of Pi, on the other hand. Whole animal experiments, the isolated kidney preparation, micropuncture methods and microvesicles of brush border membranes will be used to assess the transport characteristics of the renal tubule under these circumstances. The relationship between the low concentration of Pi and renal energy metabolism in the newborn and the relative contribution of oxidative metabolism, glycolysis and gluconeogenesis to this process will also be tested. Measurements of adenine nucleotides will be performed by high pressure liquid chromatography (HPLC) and nuclear magnetic resonance (NMR). It is reasonable to assume that an increase in the availability of Pi will increase the intracellular pool of adenine nucleotides and Pi and diminish the turnover rate. The studies described should permit us to elucidate the mechanisms accounting for the increased rate of renal tubular reabsorption of Pi during development and to understand abnormalities in renal transport of Pi such as those encountered in hypophosphatemic rickets.
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