Calcimimetic compound upregulates decreased calcium-sensing receptor expression level in parathyroid glands of rats with chronic renal insufficiency
Calcimimetic compound upregulates decreased calcium-sensing receptor expression level in parathyroid glands of rats with chronic renal insufficiency
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DOI：
10.1097/01.asn.0000141016.20133.33
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发表时间：
2004-10-01
影响因子：
13.6
通讯作者：
Akizawa, T
中科院分区：
文献类型：
--
作者：
Mizobuchi, M;Hatamura, I;Akizawa, T
钙敏感受体（CaR）的表达水平降低归因于甲状旁腺细胞对细胞外钙浓度[Ca2+](o)的低敏感性，这在慢性肾功能不全（CRI）患者和大鼠继发性甲状旁腺功能亢进（SHPT）的发病机制中起着至关重要的作用。拟钙化化合物已被证明可以改善CaR对细胞外钙浓度的敏感性，并抑制甲状旁腺激素（PTH）的过度分泌和甲状旁腺细胞的增殖。然而，钙化剂对CRI中甲状旁腺细胞中CaR表达水平降低的影响尚不清楚。本研究旨在探讨拟钙化化合物NSP R-568 （R-568）对实验性CRI大鼠甲状旁腺细胞中CaR表达的影响。采用高磷饲粮8周（n = 12； Nx-8组）或9周（n = 11； Nx-9组）诱导重度SHPT。另一组尿毒症大鼠饲喂高磷饲粮8周后，每天1次口服R-568 （100 μ mol/kg体重），连续7 d （n = 11； Nx+R-568组）。假手术大鼠饲喂标准饮食9周作为对照（n = 8）。R-568治疗导致血浆PTH水平显著降低，血清钙显著降低，血清磷浓度无变化。血清1,25(OH)2D3水平不受R-568的影响。Nx-8和Nx-9组与对照组相比，CaR mRNA和蛋白水平显著降低；然而，Nx-8组和Nx-9组在这些参数上没有显著差异。在Nx+R-568组中，与Nx-8或Nx-9组相比，CaR mRNA和蛋白水平显著升高。与Nx-9组相比，R-568能有效减少增殖细胞核抗原阳性细胞的数量，抑制甲状旁腺的生长。结果表明，拟钙化化合物R-568上调了降低的CaR表达，这种上调可能通过提高CaR对[Ca2+]的敏感性来增强PTH分泌和甲状旁腺细胞增生(o)。
The reduced expression level of the calcium-sensing receptor (CaR) is attributed to the hyposensitivity of parathyroid cells to extracellular calcium concentration [Ca2+](o) which plays a crucial role in the pathogenesis of secondary hyperparathyroidism (SHPT) in patients and rats with chronic renal insufficiency (CRI). Calcimimetic compounds have been demonstrated to improve the decreased sensitivity of CaR to extracellular calcium concentration and to suppress both parathyroid hormone (PTH) oversecretion and parathyroid cell proliferation. However, the effect of calcimimetics on the reduced CaR expression level in parathyroid cells in CRI remains unclarified. The aim of this investigation was to examine the effect of the calcimimetic compound NSP R-568 (R-568) on the CaR expression in the parathyroid cells of rats with experimental CRI. Subtotally nephrectomized rats were fed a high-phosphorus diet for 8 (n = 12; Nx-8 group) or 9 wk (n = 11; Nx-9 group) to induce severe SHPT. Another group of uremic rats were fed a high-phosphorus diet for 8 wk and then orally administered R-568 (100 mumol/kg body wt) once a day for 7 d (n = 11; Nx+R-568 group). Sham-operated rats that were fed a standard diet for 9 wk were used as controls (n = 8). R-568 treatment induced a significant reduction in plasma PTH level with significant decrease in serum calcium and without change in serum phosphorus concentration. Serum 1,25(OH)2D3 level was not affected by R-568 administration. CaR mRNA and protein levels in the Nx-8 and Nx-9 groups significantly decreased compared with those in the controls; however, no significant difference in these parameters was observed between the Nx-8 and Nx-9 groups. In the Nx+R-568 group, CaR mRNA and protein levels significantly increased compared with those in either the Nx-8 or Nx-9 group. R-568 was effective in reducing the number of proliferating cell nuclear antigen-positive cells along with parathyroid gland growth suppression in the Nx+R-568 group compared with that in the Nx-9 group. The results suggest that the calcimimetic compound R-568 upregulates decreased CaR expression, and the upregulation possibly has an enhancement effect on PTH secretion and parathyroid cell hyperplasia through the improved sensitivity of CaR to [Ca2+](o).