REGULATION OF RENAL PHOSPHATE REABSORPTION DURING GROWTH

生长过程需要充足的磷酸盐， 通常由饮食来源和减少的尿损失提供 磷酸盐。 然而，虽然众所周知，年轻，不成熟 动物在生长过程中保持正磷酸盐平衡， 肾脏中发生的促进这一过程的适应性变化， 已澄清。 本建议的主要目标是评估 发育过程中磷酸盐重吸收的肾内调节。 的 一般的假设是，为了响应新生儿的需求， 在生长过程中，肾脏在生长过程中起着核心作用。 通过限制磷酸盐的排泄来维持正磷酸盐平衡 通过增强肾小管对磷酸盐的重吸收。 无论是在 计划采用体内和体外方法。 清除和微穿刺 方法将被用来检查磷酸盐的肾单位网站 重吸收及其对饮食和激素因素的反应 调节磷酸盐体内平衡。 将在以下方面进行比较： 未成熟、断奶大鼠（34周龄）、成年大鼠（5-6月龄），以及 生长抑制的未成熟大鼠（通过慢性注射a 生长激素释放因子特异性拮抗剂）。 走上更 将进行细胞水平的放射性配体结合研究， 确定生长激素（GH）的肾受体的个体发育。 的 需要检验的具体假设是， 磷酸盐的肾内处理（与增加的重吸收有关， 直肠部、远端小管和深肾单位）导致贪婪的 生长过程中的磷酸盐重吸收。 此外，低反应 磷酸尿刺激（PTH），以及促进 磷酸盐重吸收（GH，IGF-1），共同有助于肾脏 在发育过程中保持磷酸盐。 所起的相对作用 在这些过程中，对生长和发育不成熟的需求 将使用一种新的生长激素缺乏症模型进行直接检查。 具体的方案旨在检查：a）特定的 拮抗剂下丘脑生长激素释放因子对生长和 B）年龄依赖性的 肾生长激素受体的变化，c） 磷酸盐重吸收及其与生长的关系，d）机制 未成熟大鼠对磷酸尿刺激的抵抗力，e） 抑制增长扭转某些重要趋势的可能性 适应磷酸盐保护和f）的可能性， 胰岛素样生长因子1（IGF-1）可能介导生长的影响， 激素对未成年大鼠生长和肾脏磷酸盐转运的影响。 这些研究将提供有关 肾和内分泌系统之间的相互关系， 发展，并将加强我们对肾内 适应生长的机制。

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.