MECHANISM OF HYPERCALCIURIA IN GENETIC HYPERCALCIURIA RATS

遗传性高钙尿大鼠的高钙尿机制

• 批准号: 6105570
• 负责人: DAVID A BUSHINSKY
• 金额: $ 5.03万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6105570
• 关键词: 1,25 dihydroxycholecalciferol; acetazolamide; calcium metabolism; collagen; crystallization; dietary control; disease /disorder model; furosemide; gender difference; growth factor; hypercalciuria; inhibitor /antagonist; interleukin 1; laboratory rat; nephrolithiasis; osteoblasts; osteoclasts; parathyroid hormones; pathologic process; phosphorus; physiologic bone resorption; thiazide; thrombin; tissue /cell culture

This project has the long-term objective of improving our understanding of the pathogenesis of idiopathic hypercalciuria and nephrolithiasis in man by studying genetic hypercalciuria and nephrolithiasis in the rat. We have successfully bred a colony of genetic idiopathic hypercalciuric (IH) stone forming rats, now in their 31st generation, whose daily urinary calcium excretion (UCa) is 8 to 9 times greater than controls. The mechanism of the increased UCa appears to be increased intestinal Ca absorption in addition to a smaller component of renal Ca leak and/or enhanced bone resorption. The female IH rats have greater urinary supersaturation with respect to brushite (CaHPO4) and have a greater kidney Ca content than either normocalciuric females or males or IH males. After eating standard rat chow for 4 months, 12 of 19 female and 5 of 5 male IH rats had renal and/or ureteral calcifications and many of these had hydronephrosis. There was no calcification or hydronephrosis in any of 10 controls. These IH rats appear to be an excellent model of human idiopathic hypercalciuria; however with the IH rat we are able to precisely regulate dietary ionic constituents to a degree not possible in humans and thus are able to critically control the extent and duration of urinary ion excretion and thus supersaturation with respect to individual ionic complexes. We propose to test the following hypotheses: 1) That stone formation and nephrocalcinosis in the IH rat is a function of urinary supersaturation and time by determining a) the degree and type of urinary saturation and time necessary for stone formation, b) the independent role of gender in stone formation, c) the independent role of citrate in stone formation and d) the role of thiazides, furosemide and acetazolamide in altering supersaturation and stone formation in IH rats. 2) That differences in crystallization inhibitors Tamm-Horsfall protein and/or nephrocalcin explain why only some IH rats form stones despite equivalent supersaturation for similar periods of time by a) comparison of inhibitor activity in normocalciuric control and IH rats, b) comparing the inhibitor activity in IH rats that do and do not form stones and c) determining the effect of alterations of magnitude and type of urinary supersaturation on inhibitor activity. 3) That bone from IH rats has a greater sensitivity to 1,25(OH)2D3 but not to other calcitropic agents compared to bone from control rats by a) culturing isolated neonatal rat calvariae from control and IH rats with and without 1,25(OH)2D3, and other calcitropic agents to measure basal and stimulated bone resorption b) comparing basal and stimulated osteoclastic and osteoblastic activity in bones from control and IH rats. 4) That there is abnormal in vivo regulation of serum 1,25(OH)2D3 in IH rats by determining the dynamic regulation of serum 1,25(OH)2D3 ionized Ca serum phosphorus and PTH.

该项目的长期目标是提高我们对 人类特发性高钙尿和肾结石的发病机理 通过研究大鼠中的遗传性高钙尿和肾结石病。我们有 成功地繁殖了一个遗传特发性高钙尿液（IH）石头的殖民地 形成的老鼠，现在是他们的第31代，每天的尿钙 排泄物（UCA）是对照组的8至9倍。机制 增加的UCA似乎是增加的肠道Ca吸收 除了肾脏CA泄漏和/或增强骨骼的较小组件外 吸收。雌性IH大鼠具有更大的尿过度饱和 尊重Brushite（Cahpo4），并且肾脏CA的含量比 正常的女性，雄性或IH男性。进食标准后 大鼠chow 4个月，19名女性中的12名和5名男性IH大鼠中的5个有肾脏 和/或输尿管钙化，其中许多都有肤色。那里 在10个对照中的任何一个中均未钙化或肾积水。这些IH 大鼠似乎是人类特发性高钙尿症的出色模型。 但是，使用IH大鼠，我们能够精确调节饮食离子 人类不可能的一定程度成分，因此能够 批判性地控制尿离子排泄的程度和持续时间 因此，相对于单个离子复合物过饱和。我们 提议检验以下假设：1）石头形成和 IH大鼠中的肾球腺钙化是泌尿过饱和的函数 通过确定a）尿饱和度的程度和类型和时间 石材形成所需的时间，b）性别在 石材形成，c）柠檬酸盐在石材形成和 d）噻嗪类，速尿和乙酰唑胺在改变 IH大鼠的过饱和石材形成。 2）差异 结晶抑制剂TAMM-HORSFALL蛋白和/或肾红细胞素 解释为什么尽管等效，但只有某些IH大鼠仍会形成石头 通过a）比较抑制剂在相似时期过饱和 在正核对控制和IH大鼠中的活性，b）比较抑制剂 在IH大鼠中的活动和不形成石头，c）确定 幅度变化和尿液过饱和类型的影响 抑制剂活性。 3）IH大鼠的骨头对 1,25（OH）2d3，但与其他钙屈剂相比，与其他骨化剂相比 通过a）对照培养孤立的新生大鼠钙的控制大鼠 带有和没有1,25（OH）2d3的IH大鼠，以及其他钙的剂 测量基础和刺激的骨吸收b）比较基础和 骨骼中刺激的整骨和成骨细胞活性 和我的老鼠。 4）血清体内调节异常 通过确定血清的动态调节，IH大鼠的1,25（OH）2d3 1,25（OH）2d3离子化的Ca血清磷和PTH。