Mizobuchi Masahide, Hatamura Ikuji, Ogata Hiroaki, Saji Fumie, Uda Susumu, Shiizaki Kazuhiro, Sakaguchi Toshifumi, Negi Shigeo, Kinugasa Eriko, Koshikawa Shozo, Akizawa Tadao
Center for Blood Purification Therapy, Wakayama Medical University, Japan.
J Am Soc Nephrol. 2004 Oct;15(10):2579-87. doi: 10.1097/01.ASN.0000141016.20133.33.
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 micromol/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.
钙敏感受体（CaR）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）的发病机制中起关键作用。已证明拟钙剂化合物可改善CaR对细胞外钙浓度的降低敏感性，并抑制甲状旁腺激素（PTH）分泌过多和甲状旁腺细胞增殖。然而，拟钙剂对CRI患者甲状旁腺细胞中CaR表达水平降低的影响仍不清楚。本研究的目的是研究拟钙剂化合物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。将次全肾切除的大鼠喂以高磷饮食8周（n = 12；Nx-8组）或9周（n = 11；Nx-9组）以诱导严重的SHPT。另一组尿毒症大鼠喂以高磷饮食8周，然后每天口服R-568（100 μmol/kg体重），持续7天（n = 11；Nx+R-568组）。将喂以标准饮食9周的假手术大鼠用作对照（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给药的影响。与对照组相比，Nx-8组和Nx-9组的CaR mRNA和蛋白水平显著降低；然而，Nx-8组和Nx-9组之间在这些参数上未观察到显著差异。在Nx+R-568组中，与Nx-8组或Nx-9组相比，CaR mRNA和蛋白水平显著升高。与Nx-9组相比，R-568在Nx+R-568组中有效减少增殖细胞核抗原阳性细胞数量并抑制甲状旁腺生长。结果表明，拟钙剂化合物R-568上调降低的CaR表达，并且这种上调可能通过提高CaR对[Ca2+]o的敏感性对PTH分泌和甲状旁腺细胞增生产生增强作用。
