PTH-independent regulation of blood calcium concentration by the calcium-sensing receptor
PTH-independent regulation of blood calcium concentration by the calcium-sensing receptor
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DOI：
10.1172/jci57407
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发表时间：
2012-09-01
影响因子：
15.9
通讯作者：
Houillier, Pascal
中科院分区：
文献类型：
--
作者：
Loupy, Alexandre;Ramakrishnan, Suresh Krishna;Houillier, Pascal
许多关键的生物功能需要严格调节钙水平。甲状旁腺细胞表达的Ca2+敏感受体（CaSR）通过调节甲状旁腺激素（PTH）的分泌来控制血钙浓度。然而，CaSR也在其他器官中表达，例如肾脏，但甲状旁腺外CaSR在钙代谢中的重要性仍不清楚。在这里，我们使用甲状腺甲状旁腺切除、补充 PTH 的大鼠研究了甲状旁腺外 CaSR 的作用。长期抑制 CaSR 选择性增加肾小管钙吸收和血钙浓度，与 PTH 分泌变化无关，并且不改变肠钙吸收。 CaSR 抑制增加了用双膦酸盐预处理的动物的血钙浓度，表明这种增加不是由骨钙释放引起的。肾 CaSR 主要表达于 Henle 袢厚升肢 (TAL)。通过皮质 TAL 的体外微灌注测量，CaSR 抑制剂增加了钙重吸收和细胞旁通路通透性，但没有改变 NaCl 重吸收。我们得出结论，CaSR 是血钙浓度的直接决定因素，与 PTH 无关，并通过细胞旁途径的通透性调节 TAL 中的肾小管钙转运。这些发现表明，CaSR 抑制剂可能为与 PTH 分泌受损相关的疾病（例如原发性甲状旁腺功能减退症）提供新的特异性治疗方法。
Tight regulation of calcium levels is required for many critical biological functions. The Ca2+-sensing receptor (CaSR) expressed by parathyroid cells controls blood calcium concentration by regulating parathyroid hormone (PTH) secretion. However, CaSR is also expressed in other organs, such as the kidney, but the importance of extraparathyroid CaSR in calcium metabolism remains unknown. Here, we investigated the role of extraparathyroid CaSR using thyroparathyroidectomized, PTH-supplemented rats. Chronic inhibition of CaSR selectively increased renal tubular calcium absorption and blood calcium concentration independent of PTH secretion change and without altering intestinal calcium absorption. CaSR inhibition increased blood calcium concentration in animals pretreated with a bisphosphonate, indicating that the increase did not result from release of bone calcium. Kidney CaSR was expressed primarily in the thick ascending limb of the loop of Henle (TAL). As measured by in vitro microperfusion of cortical TAL, CaSR inhibitors increased calcium reabsorption and paracellular pathway permeability but did not change NaCl reabsorption. We conclude that CaSR is a direct determinant of blood calcium concentration, independent of PTH, and modulates renal tubular calcium transport in the TAL via the permeability of the paracellular pathway. These findings suggest that CaSR inhibitors may provide a new specific treatment for disorders related to impaired PTH secretion, such as primary hypoparathyroidism.