The calcium-sensing receptor: a key factor in the pathogenesis of secondary hyperparathyroidism

Abstract

Serum calcium levels are regulated by the action of parathyroid hormone (PTH). Major drivers of PTH hypersecretion and parathyroid cell proliferation are the hypocalcemia and hyperphosphatemia that develop in chronic kidney disease patients with secondary hyperparathyroidism (SHPT) as a result of low calcitriol levels and decreased kidney function. Increased PTH production in response to systemic hypocalcemia is mediated by the calcium-sensing receptor (CaR). Furthermore, as SHPT progresses, reduced expression of CaRs and vitamin D receptors (VDRs) in hyperplastic parathyroid glands may limit the ability of calcium and calcitriol to regulate PTH secretion. Current treatment for SHPT includes the administration of vitamin D sterols and phosphate binders. Treatment with vitamin D is initially effective, but efficacy often wanes with further disease progression. The actions of vitamin D sterols are undermined by reduced expression of VDRs in the parathyroid gland. Furthermore, the calcemic and phosphatemic actions of vitamin D mean that it has the potential to exacerbate abnormal mineral metabolism, resulting in the formation of vascular calcifications. Effective new treatments for SHPT that have a positive impact on mineral metabolism are clearly needed. Recent research shows that drugs that selectively target the CaR, calcimimetics, have the potential to meet these requirements.

Involvement of the Calcium-sensing Receptor in Human Taste Perception

“…Cinacalcet (13) and NPS-2143 (14) were chemically synthesized by methods described in the literature, and their activity was determined using HEK-293 cells that were transiently transformed with the human CaSR (hCaSR). All other reagents were a special purity grade purchased from Sigma-Aldrich Japan.…”

“…The total RNA was isolated from the epithelial papillae and from the epithelium without taste buds (RNA micro kit, Stratagene). The purified RNA was denatured at 60°C for 5 min, and first-strand cDNA was synthesized at 50°C for 60 min using oligo(dT) [12][13][14][15][16][17][18] primer and reverse transcriptase (SuperScript III, Invitrogen) in a final volume of 20 l. After synthesizing the cDNA, 1 l of cDNA was used as a template in 20 l of PCR mixture with Taq polymerase (Invitrogen). The PCR conditions were as follows: 94°C for 2 min and 29 -35 cycles at 94°C for 30 s, 58°C for 20 s, and 72°C for 45 s. The PCR products were analyzed by gel electrophoresis (2% agarose gel) with GelRed staining (Biotium).…”

Oral Phosphorus Supplementation Secondarily Increases Circulating Fibroblast Growth Factor 23 Levels at Least Partially via Stimulation of Parathyroid Hormone Secretion

“…The dose of phosphorus was equivalent to approximately one-third of the daily phosphorus intake of rats. The dose of CIN was determined based on the previous studies (16,17), which showed that oral CIN administration at 30 mg/kg substantially decreased serum levels of intact PTH until 12 or 24 h after administration in normal rats. The dose of hPTH (1-34) was determined based on the study of Li et al (18), which reported that normal rats receiving subcutaneous injection of hPTH (1-34) at 80 mg/ kg showed approximately 50 pg/mL of serum hPTH (1-34) levels at 1 h after injection.…”

Dynamics of Parathyroid Hormone Secretion in Health and Secondary Hyperparathyroidism

“…In clinical disorders such as CKD, vitamin D deficiency, and primary hyperparathyroidism, an increase in parathyroid gland mass from hyperplasia in the former two disorders or an adenoma in most cases of primary hyperparathyroidism is associated with increases in the maximal PTH response to hypocalcemia (18,19,30,33,67). In CKD, calcitriol and its analogs decrease PTH transcription and upregulate vitamin D receptors (68); therefore, it is not surprising that prolonged calcitriol treatment in CKD often results in a reduction in maximal PTH values (69,70). Moreover, treatment with calcitriol besides reducing iPTH values may enhance the intraglandular degradation of iPTH (71).…”