REGULATION OF RENAL PHOSPHATE REABSORPTION DURING GROWTH

生长过程需要充足的磷酸盐供应，这是 通常从饮食来源和减少尿液损失两个方面提供 磷酸盐。然而，尽管众所周知，年轻、不成熟 动物在生长过程中保持正的磷酸盐平衡， 肾脏中发生的促进这一过程的适应并没有 已经被澄清了。这项提案的总体目标是评估 发育过程中肾内磷酸盐重吸收的调节。这个 一般的假设是，为了响应新生儿对 在生长过程中，肾脏在体内起着核心作用 通过限制磷酸盐的排泄来维持正磷平衡 通过增强管状重吸收磷酸盐来促进磷酸盐。两个都在 计划采用体内和体外方法。清除和微穿刺术 方法将用来检查磷酸盐的肾单位 重吸收及其对饮食和激素因素的反应 调节磷酸盐动态平衡。我们将比较以下几个方面： 未成熟的断奶大鼠(34周龄)，成年大鼠(5-6月龄)，以及 生长抑制幼鼠(慢性注射A 生长激素释放因子的特异性拮抗剂)。在更多的 在细胞水平上，将进行放射性配基结合研究 确定生长激素(GH)肾脏受体的个体发育。这个 需要检验的具体假设是， 肾内磷酸盐的处理(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 生长过程中磷酸盐的再吸收。此外，对此反应迟钝 磷酸尿酸刺激(PTH)以及促进 磷酸盐重吸收(GH、IGF-1)，共同促进肾脏 发育过程中磷酸盐的滞留。所扮演的相对角色 在这些过程中，对增长的需求与发展的不成熟 将使用一种新的生长激素缺乏模型直接进行检查。 特定协议旨在检查：a)特定协议的影响 下丘脑生长激素释放因子拮抗剂对生长发育的影响 关于发育过程中肾脏磷酸盐的动态平衡，b)年龄相关 肾生长激素受体的变化，c)肾单位部位 磷酸盐重吸收及其与生长的关系，d)机理 幼鼠对磷酸尿酸刺激的抵抗力，e) 经济增长的抑制可能会逆转某些重要的 适应磷酸盐守恒和f)有可能 胰岛素样生长因子-1(IGF-1)可能介导生长效应 激素对幼鼠生长和肾脏磷酸盐转运的影响。 这些研究将提供有关 肾脏和内分泌系统之间的相互关系 发展，并将增进我们对肾内的了解 参与适应生长的机制。

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.