Direct upregulation of parathyroid calcium-sensing receptor and vitamin D receptor by calcimimetics in uremic rats

Abstract

Tejero E, Rodriguez M. Direct upregulation of parathyroid calciumsensing receptor and vitamin D receptor by calcimimetics in uremic rats. Am J Physiol Renal Physiol 296: F605-F613, 2009. First published December 17, 2008 doi:10.1152/ajprenal.90272.2008.-To investigate whether the effect of the calcimimetic AMG 641 and calcitriol on CaSR and VDR expression could be separated from their ability to reduce parathyroid cell proliferation, five-sixth nephrectomized (5/6 Nx) rats received vehicle, AMG 641, calcitriol, or AMG 641ϩcalcit-riol either daily for 13 days (long-term protocol) or in a single dose (short-term protocol). In the long-term protocol, AMG 641, calcitriol, and their combination significantly reduced the percentage of proliferating parathyroid cells. Proliferation was uncontrolled in the shortterm protocol. A significant increase in CaSR mRNA (% vs. ␤-actin) was detected in rats treated with both calcitriol (1.60 Ϯ 0.30) and AMG 641 (1.66 Ϯ 0.25) for 13 days (P ϭ 0.01 vs. 5/6 Nxϩvehicle, 0.89 Ϯ 0.09); and there was a further increase when both drugs were administered simultaneously (2.46 Ϯ 0.33). In the short-term protocol, only rats receiving AMG 641 alone (2.01 Ϯ 0.33, P Ͻ 0.001) showed increased expression of CaSR mRNA, whereas the combination (1.81 Ϯ 0.20) produced no additional benefit. AMG 641 also increased CaSR mRNA expression in vitro. Changes in VDR mRNA paralleled those of CaSR mRNA. In the long-term treatment, both AMG 641 (0.87 Ϯ 0.14) and calcitriol (0.99 Ϯ 0.12) increased VDR mRNA (P Ͻ 0.05 vs. 5/6 Nxϩvehicle, 0.49 Ϯ 0.10), and the increase was more accentuated when the drugs were combined (1.49 Ϯ 0.45). In the short-term protocol, only treatment with AMG 641, alone (1.52 Ϯ 0.41) or combined with calcitriol (1.86 Ϯ 0.24), increased VDR mRNA. In conclusion, our results demonstrate an acute increase in CaSR mRNA and VDR mRNA in the parathyroid glands of uremic rats treated with AMG 641, in which cell proliferation was uncontrolled, thus supporting a direct effect of calcimimetics on CaSR and VDR expression by hyperplastic parathyroid cells.hyperparathyroidism; PTH; hyperplasia; calcium and calcitriol REGULATION OF MINERAL METABOLISM involves the interaction of multiple organ systems, notably bone and kidneys, and multiple endocrine factors. One such factor is parathyroid hormone (PTH), which, when elevated, is the primary characteristic of secondary hyperparathyroidism (HPT). A predominant feature of secondary HPT is progressive parathyroid gland hyperplasia (12) with concomitantly decreased expression of the calciumsensing receptor (CaSR) (4, 18) and vitamin D receptor (VDR) (15,26). The downregulation of these receptors is an important pathogenic process in the progression of secondary HPT (5,15).

FGF23 Fails to Inhibit Uremic Parathyroid Glands

“…An upregulation of VDR and CaR was also observed in parathyroid glands incubated with a high Ca concentration; these results confirm previous published observations. 12,13 The addition of FGF23 to high Ca did not further increase the expression of parathyroid CaR and VDR. In uremic hyperplastic parathyroid glands, the expression of VDR and CaR is reduced 14 -16 ; the administration of FGF23 to rats with renal failure failed to increase parathyroid ERK1/2 activity and did not have an effect on the expression of VDR or CaR.…”

Cinacalcet Upregulates Calcium-Sensing Receptors of Parathyroid Glands in Hemodialysis Patients

“…CaSR downregulation has been demonstrated in hyperplastic parathyroid glands from patients with SHPT, particularly in glands with nodular hyperplasia, and has shown to be associated with the high proliferative activity of parathyroid glands and the progression of SHPT [9,12]. Cinacalcet, an allosteric modulator of the CaSR, increases the sensitivity of CaSRs to activation by extracellular calcium, and thus reduces PTH secretion, while simultaneously lowering the serum levels of phosphorus, calcium, and calcium-phosphorus products in patients with SHPT [6,7].…”

“…Cinacalcet, an allosteric modulator of the CaSR, increases the sensitivity of CaSRs to activation by extracellular calcium, and thus reduces PTH secretion, while simultaneously lowering the serum levels of phosphorus, calcium, and calcium-phosphorus products in patients with SHPT [6,7]. In uremic rats, cinacalcet has been demonstrated to upregulate the decreased CaSR expression in the parathyroid glands, and ‘sensitize' them to extracellular calcium, its main regulator, through increased expression of the CaSR [8,9]. However, to date, the effect of cinacalcet on the reduced CaSR expression in human hyperplastic parathyroid glands has remained to be elucidated.…”

“…In uremic rats, cinacalcet has been demonstrated to upregulate the decreased CaSR expression level in the parathyroid glands and ‘sensitize' the glands to extracellular calcium as the main regulator, through increased expression of the CaSR [8,9]. However, the effect of cinacalcet on the reduced CaSR expression in human parathyroid glands remains to be elucidated.…”

Novel regulatory aspects of the extracellular Ca2+-sensing receptor, CaR

“…Furthermore, loss of CaR expression has been observed in hyperparathyroidism secondary to renal failure, which contributes to the insensitivity of parathyroid glands to hypercalcaemia and hyperphosphataemia and which evokes parathyroid gland hyperplasia [15,23,67]. Treatment of secondary hyperparathyroidism with calcimimetics improves the clinical outcome of patients with chronic kidney disease by restoring CaR expression levels and by reducing both serum PTH levels and parathyroid hyperplasia [85,87]. Based on these considerations, while to date no drug has been approved for the treatment of diseases resulting from inherited mutations or polymorphisms of the CaR, one would anticipate the use of pharmacological modulators of CaR function for symptomatic diseases resulting from an altered CaR expression and/or function.…”