Division of Nephrology, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
Am J Physiol Renal Physiol. 2013 Mar 15;304(6):F718-26. doi: 10.1152/ajprenal.00645.2012. Epub 2013 Jan 23.
Genetic hypercalciuric stone-forming (GHS) rats, bred to maximize urine (U) calcium (Ca) excretion, have increased intestinal Ca absorption and bone Ca resorption and reduced renal Ca reabsorption, leading to increased UCa compared with the Sprague-Dawley (SD) rats. GHS rats have increased vitamin D receptors (VDR) at each of these sites, with normal levels of 1,25(OH)(2)D(3) (1,25D), indicating that their VDR is undersaturated with 1,25D. We tested the hypothesis that 1,25D would induce a greater increase in UCa in GHS rats by feeding both strains ample Ca and injecting 1,25D (25 ng · 100 g body wt(-1) · day(-1)) or vehicle for 16 days. With 1,25D, UCa in SD increased from 1.7 ± 0.3 mg/day to 24.4 ± 1.2 (Δ = 22.4 ± 1.5) and increased more in GHS from 10.5 ± 0.7 to 41.9 ± 0.7 (Δ = 29.8 ± 1.8; P = 0.003). To determine the mechanism of the greater increase in UCa in GHS rats, we measured kidney RNA expression of components of renal Ca transport. Expression of transient receptor potential vanilloid (TRPV)5 and calbindin D(28K) were increased similarly in SD + 1,25D and GHS + 1,25D. The Na(+)/Ca(2+) exchanger (NCX1) was increased in GHS + 1,25D. Klotho was decreased in SD + 1,25D and GHS + 1,25D. TRPV6 was increased in SD + 1,25D and increased further in GHS + 1,25D. Claudin 14, 16, and 19, Na/K/2Cl transporter (NKCC2), and secretory K channel (ROMK) did not differ between SD + 1,25D and GHS + 1,25D. Increased UCa with 1,25D in GHS exceeded that of SD, indicating that the increased VDR in GHS induces a greater biological response. This increase in UCa, which must come from the intestine and/or bone, must exceed any effect of 1,25D on TRPV6 or NCX1-mediated renal Ca reabsorption.
遗传高钙尿结石形成（GHS）大鼠，经培育最大限度地提高尿（U）钙（Ca）排泄，具有增加肠道 Ca 吸收和骨 Ca 重吸收，减少肾 Ca 重吸收的特点，导致 UCa 与 Sprague-Dawley（SD）大鼠相比增加。GHS 大鼠在这些部位的维生素 D 受体（VDR）都增加，1,25（OH）（2）D（3）（1,25D）水平正常，表明其 VDR 与 1,25D 不饱和。我们通过给两种品系大鼠喂食充足的 Ca，并注射 1,25D（25ng·100g 体重-1·天-1）或载体 16 天，来检验 1,25D 会诱导 GHS 大鼠 UCa 增加更多的假设。用 1,25D，SD 的 UCa 从 1.7±0.3mg/天增加到 24.4±1.2（Δ=22.4±1.5），GHS 增加更多，从 10.5±0.7 增加到 41.9±0.7（Δ=29.8±1.8；P=0.003）。为了确定 GHS 大鼠 UCa 增加更多的机制，我们测量了肾脏 Ca 转运的组成部分的肾 RNA 表达。SD+1,25D 和 GHS+1,25D 中瞬时受体电位香草酸（TRPV）5 和钙结合蛋白 D（28K）的表达相似增加。在 GHS+1,25D 中增加了 Na+/Ca2+交换器（NCX1）。Klotho 在 SD+1,25D 和 GHS+1,25D 中减少。TRPV6 在 SD+1,25D 中增加，并在 GHS+1,25D 中进一步增加。Claudin 14、16 和 19、Na/K/2Cl 转运体（NKCC2）和分泌性 K 通道（ROMK）在 SD+1,25D 和 GHS+1,25D 之间没有差异。在 GHS 中，1,25D 引起的 UCa 增加超过 SD，表明 GHS 中增加的 VDR 诱导了更大的生物学反应。这种 UCa 的增加，必须来自肠道和/或骨骼，必须超过 1,25D 对 TRPV6 或 NCX1 介导的肾 Ca 重吸收的任何影响。
