REGULATION OF RENAL PHOSPHATE REABSORPTION DURING GROWTH

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The process of growth requires an adequate supply of phosphate, which normally is provided from both dietary sources and reduced urinary losses of phosphate. However, while it is well-known that young, immature animals maintain positive phosphate balance during growth, the adaptations that occur in the kidney to facilitate this process have not been clarified. The broad objective of this proposal is to evaluate the intrarenal regulation of phosphate reabsorption during development. The general hypothesis is that, in response to the demand of the neonate for phosphate during growth, the kidney plays a central role in the maintenance of positive phosphate balance by limiting the excretion of phosphate through enhanced tubular reabsorption of phosphate. Both in vivo and in vitro approaches are planned. Clearance and micropuncture methods will be used to examine the nephron sites of phosphate reabsorption and their response to dietary and hormonal factors regulating phosphate homeostasis. Comparisons will be made between immature, weaned rats (34 weeks old), adult rats (5-6 months old), and growth-suppressed immature rats (induced by chronic injection of a specific antagonist to growth hormone-releasing factor). On a more cellular level, radioligand binding studies will be performed to determine the ontogeny of renal receptors for growth hormone (GH). The specific hypotheses to be tested are that intrinsic changes in the intrarenal handling of phosphate (related to increased reabsorption in the pars recta, distal tubule, and deep nephrons) result in avid phosphate reabsorption during growth. Furthermore, hyporesponsiveness to phosphaturic stimuli (PTH), and the presence of factors that promote phosphate reabsorption (GH, IGF-1), collectively contribute to the renal retention of phosphate during development. The relative roles played by the demands for growth versus developmental immaturity in these processes will be directly examined using a new model of growth hormone deficiency. Specific protocols are designed to examine: a) the effects of a specific antagonist to hypothalamic growth hormone-releasing factor on growth and on renal phosphate homeostasis during development, b) the age-dependent changes in renal growth hormone receptors, c) the nephron sites of phosphate reabsorption and their relationship to growth, d) the mechanism of resistance of immature rats to phosphaturic stimuli, e) the possibility that the suppression of growth reverses certain important adaptations for phosphate conservation and f) the possibility that insulin-like growth factor 1 (IGF-1) may mediate the effects of growth hormone on growth and renal phosphate transport in the immature rat. These studies will provide important information regarding the interrelationship between the renal and endocrine system&, during development, and will enhance our understanding of the intrarenal mechanisms involved in the adaptations for growth.