Univ. of Rochester School of Medicine and Dentistry, Div. of Nephrology, Dept. of Medicine, 601 Elmwood Ave., Box 675, Rochester, NY 14642.
Am J Physiol Renal Physiol. 2013 Oct 15;305(8):F1132-8. doi: 10.1152/ajprenal.00296.2013. Epub 2013 Aug 7.
The inbred genetic hypercalciuric stone-forming (GHS) rats exhibit many features of human idiopathic hypercalciuria and have elevated levels of vitamin D receptors (VDR) in calcium (Ca)-transporting organs. On a normal-Ca diet, 1,25(OH)2D3 (1,25D) increases urine (U) Ca to a greater extent in GHS than in controls [Sprague-Dawley (SD)]. The additional UCa may result from an increase in intestinal Ca absorption and/or bone resorption. To determine the source, we asked whether 1,25D would increase UCa in GHS fed a low-Ca (0.02%) diet (LCD). With 1,25D, UCa in SD increased from 1.2 ± 0.1 to 9.3 ± 0.9 mg/day and increased more in GHS from 4.7 ± 0.3 to 21.5 ± 0.9 mg/day (P < 0.001). In GHS rats on LCD with or without 1,25D, UCa far exceeded daily Ca intake (2.6 mg/day). While the greater excess in UCa in GHS rats must be derived from bone mineral, there may also be a 1,25D-mediated decrease in renal tubular Ca reabsorption. RNA expression of the components of renal Ca transport indicated that 1,25D administration results in a suppression of klotho, an activator of the renal Ca reabsorption channel TRPV5, in both SD and GHS rats. This fall in klotho would decrease tubular reabsorption of the 1,25D-induced bone Ca release. Thus, the greater increase in UCa with 1,25D in GHS fed LCD strongly suggests that the additional UCa results from an increase in bone resorption, likely due to the increased number of VDR in the GHS rat bone cells, with a possible component of decreased renal tubular calcium reabsorption.
近交遗传高钙尿结石形成（GHS）大鼠表现出许多人类特发性高钙尿的特征，并且在钙转运器官中维生素 D 受体（VDR）水平升高。在正常钙饮食中，1,25（OH）2D3（1,25D）在 GHS 中比在对照（Sprague-Dawley（SD））中更能增加尿（U）Ca。额外的 UCa 可能是由于肠道 Ca 吸收和/或骨吸收增加所致。为了确定来源，我们询问 1,25D 是否会增加喂食低钙（0.02％）饮食（LCD）的 GHS 中的 UCa。用 1,25D，SD 中的 UCa 从 1.2±0.1 增加到 9.3±0.9mg/天，而 GHS 中的 UCa 从 4.7±0.3 增加到 21.5±0.9mg/天（P<0.001）。在有或没有 1,25D 的情况下，LCD 上的 GHS 大鼠的 UCa 远远超过每日 Ca 摄入量（2.6mg/天）。尽管 GHS 大鼠的 UCa 中存在更大的过量，但其必须来自骨矿物质，也可能存在 1,25D 介导的肾小管 Ca 重吸收减少。肾脏 Ca 转运的组成部分的 RNA 表达表明，1,25D 给药导致肾脏 Ca 重吸收通道 TRPV5 的激活剂 klotho 在 SD 和 GHS 大鼠中的表达受到抑制。klotho 的这种下降会降低 1,25D 诱导的骨 Ca 释放的管状重吸收。因此，在喂食 LCD 的 GHS 大鼠中，1,25D 的 UCa 增加更多强烈表明，额外的 UCa 是由于骨吸收增加所致，这可能是由于 GHS 大鼠骨细胞中 VDR 数量增加所致，可能与肾小管 Ca 重吸收减少有关。
