Contribution of increased VDR and CaR to Hypercalciuria in the GHS Rat

VDR 和 CaR 增加对 GHS 大鼠高钙尿症的影响

• 批准号: 8036042
• 负责人: DAVID A BUSHINSKY
• 金额: $ 28.85万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-15 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8036042
• 关键词: Acute; Alendronate; Animal Model; Animals; Area; Blood; Bone Resorption; Calcitriol; Calcium; Calcium-Sensing Receptors; Calculi; Defect; Diet; Dose; Equilibrium; Excretory function; Functional disorder; Genetic; Human; Inherited; Intestines; Investigation; Kidney; Kidney Calculi; Lead; Measures; Metabolic; Minerals; Modeling; Nephrolithiasis; Normal Range; Organ; Patient Care; Physiological; Physiology; Protocols documentation; Publishing; Rattus; Renal tubule structure; Research; Research Design; Role; Serum; Severities; Sprague-Dawley Rats; Testing; Therapeutic; Therapeutic Intervention; Tissues; Tubular formation; Urine; Variant; Vitamin D; Vitamin D Deficiency; Vitamin D3 Receptor; absorption; base; bone; bone loss; calcium absorption; cinacalcet; falls; feeding; hypercalciuria; improved; receptor; response; urolithiasis; Acute; Alendronate; Animal Model; Animals; Area; Blood; Bone Resorption; Calcitriol; Calcium; Calcium-Sensing Receptors; Calculi; Defect; Diet; Dose; Equilibrium; Excretory function; Functional disorder; Genetic; Human; Inherited; Intestines; Investigation; Kidney; Kidney Calculi; Lead; Measures; Metabolic; Minerals; Modeling; Nephrolithiasis; Normal Range; Organ; Patient Care; Physiological; Physiology; Protocols documentation; Publishing; Rattus; Renal tubule structure; Research; Research Design; Role; Serum; Severities; Sprague-Dawley Rats; Testing; Therapeutic; Therapeutic Intervention; Tissues; Tubular formation; Urine; Variant; Vitamin D; Vitamin D Deficiency; Vitamin D3 Receptor; absorption; base; bone; bone loss; calcium absorption; cinacalcet; falls; feeding; hypercalciuria; improved; receptor; response; urolithiasis

DESCRIPTION (provided by applicant): Humans with idiopathic hypercalciuria (IH), the most common metabolic abnormality associated with human nephrolithiasis, and genetic hypercalciuric stone-forming (GHS) rats share a common physiology: high urine (U) calcium (Ca) excretion, high intestinal Ca absorption, reduced renal Ca reabsorption and, with low Ca diet (LCD), loss of bone mineral. Both have excessive vitamin D receptor (VDR) abundance. Administration of 1,25(OH)2D3 (1,25D3) to normal (nl) humans or rats leads to physiology that mimics IH and the GHS rat. In the 1st aim we will test the hypothesis that the hypercalciuria in GHS rats results from an inherited increase in VDR abundance so that 1,25D3 response is elevated, given nl 1,25D3 levels, leading to a form of endogenous 1,25D3 excess. If true, then vitamin D deficiency of graded severity should bring responses of the GHS rat into the nl range with respect to UCa, intestinal Ca absorption, and bone mineral balance. In vitamin D deficient GHS and Sprague-Dawley (SD) rats repleted with graded amounts of 1,25D3 below and above the physiological range, we will measure UCa, intestinal Ca absorption and VDR on a nl Ca diet. In parallel studies GHS and SD rats will be fed LCD to virtually eliminate absorbed Ca and UCa and VDR will be measured. In other similarly treated GHS and SD rats both fed LCD and given alendronate to virtually eliminate absorbed Ca and block bone resorption we will measure UCa and VDR. In all cases, at the lowest 1,25D3 repletion ranges, UCa from GHS and SD rats should be indistinguishable. GHS rats reabsorb renal tubular Ca less well than SD at fixed and equal PTH, Ca levels, and filtered loads of Ca. Renal cortical Ca sensing receptor (CaR) abundance is elevated in GHS rats, and its stimulation reduces Ca reabsorption in nl rats. 1,25D3, through VDR, can increase CaR. In the 2nd aim we will test the hypothesis that the high VDR of GHS rats leads to high renal CaR abundance resulting in reduced Ca reabsorption at nl blood Ca2+. If true, in the absence of PTH increasing blood Ca2+ should lower renal Ca reabsorption to a greater extent in GHS than in SD rats. Moreover, D depletion should reduce the difference of renal Ca reabsorption between GHS and SD rats to an indistinguishable level. In vitamin D replete, parathyroidectomized GHS and SD rats, we will vary blood Ca2+ from below to above the physiological range and calculate Ca fractional reabsorption during an acute clearance study and measure CaR and VDR. If CaR is a primary mechanism for reduced Ca reabsorption in GHS rats, then reabsorption should fall more in GHS than in SD. We will repeat the protocol in D depleted GHS and SD rats with varying degrees of 1,25D3 repletion. If VDR-driven excess of renal CaR is a main regulator, then at the lowest levels of 1,25D3 repletion the response of renal Ca reabsorption to blood Ca2+ of GHS and SD should be indistinguishable. These studies will advance IH research and may ultimately lead to improved care of patients with urolithiasis.Excess urine calcium excretion, hypercalciuria, is the most common metabolic abnormality associated with kidney stones in humans. We have developed an animal model of hypercalciuria and propose to use these rats to determine if increases in receptors for vitamin D and/or for calcium are responsible, at least in part, for the hypercalciuria. These studies will advance research on hypercalciuria and may ultimately lead to improved care of patients with kidney stones.

DESCRIPTION (provided by applicant): Humans with idiopathic hypercalciuria (IH), the most common metabolic abnormality associated with human nephrolithiasis, and genetic hypercalciuric stone-forming (GHS) rats share a common physiology: high urine (U) calcium (Ca) excretion, high intestinal Ca absorption, reduced renal Ca reabsorption and, with low Ca diet （LCD），骨矿物质的损失。两者都有过多的维生素D受体（VDR）丰度。对正常（NL）人类或大鼠的1,25（OH）2d3（1,25d3）的施用导致生理学模仿IH和GHS大鼠。在第一个目标中，我们将检验以下假设：GHS大鼠的高钙尿素是由于VDR丰度的遗传增加而导致的，因此鉴于NL 1,25d3的水平，1,25d3响应升高，导致内源性1,25d3过量的形式。如果是真的，那么分级严重程度的维生素D缺乏应将GHS大鼠的反应带入NL范围，相对于UCA，肠道CA的吸收和骨矿物质平衡。在维生素D缺乏型GHS和Sprague-Dawley（SD）大鼠中，在生理范围以下和高于生理范围以下的分级量为1,25d3，我们将在NL CA饮食中测量UCA，UCA，肠道CA的吸收和VDR。在并行研究中，将喂入LCD，以实际上消除吸收的Ca和UCA和VDR。在其他经过类似处理的GHS和SD大鼠中，均喂入LCD并给予Alendronate以实际上消除了吸收的Ca和阻断骨吸收，我们将测量UCA和VDR。在所有情况下，在最低的1,25d3补充范围内，来自GHS和SD大鼠的UCA应该是无法区分的。 GHS大鼠在固定和相等的PTH，Ca水平和过滤的CA的肾小管ca中重新吸收肾小管Ca。 GHS大鼠的肾皮质Ca感应受体（CAR）丰度升高，其刺激减少了NL大鼠的Ca重吸收。 1,25d3通过VDR可以增加汽车。在第二个目标中，我们将检验以下假设：GHS大鼠的高VDR导致高肾脏汽车丰度，从而导致NL血液Ca2+的Ca重吸收降低。如果是真的，在没有PTH的情况下，增加血液Ca2+应比SD大鼠更大程度地降低肾脏Ca的重吸收。此外，D耗竭应将GHS和SD大鼠之间的肾脏CA重吸收差异降低到无法区分的水平。在维生素D的甲状旁腺甲状腺甲状腺素和SD大鼠中，我们将在急性清除研究和测量CAR和VDR期间从下方到高于生理范围的血液Ca2+。如果CAR是降低GHS大鼠Ca重吸收的主要机制，则重新吸收的GHS应该比在SD中更多。我们将在D耗尽的GHS和SD大鼠中重复该方案，而不同程度为1,25d3的补充。如果通过VDR驱动的过量肾脏汽车是主要的调节剂，则在1,25d3的最低水平上，肾脏CA重吸收对GHS和SD的血液Ca2+的反应应该是无法区分的。这些研究将推进IH研究，并最终可能导致尿路症患者的护理。尿液钙排泄，高钙尿症，是与人类肾结石有关的最常见代谢异常。我们已经开发了一种高钙尿的动物模型，并建议使用这些大鼠来确定维生素D和/或钙的受体增加是否至少部分地是造成高钙尿症的原因。这些研究将提高对高钙的研究，并最终可能导致改善肾结石患者的护理。