Parathyroid hyperplasia in uremic rats precedes down-regulation of the calcium receptor

Ritter, Cynthia S.; Finch, Jane; Slatopolsky, Eduardo; Brown, Alex

doi:10.1046/j.1523-1755.2001.00027.x

Cited by 100 publications

(72 citation statements)

References 23 publications

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“…Thus, CaR plays a crucial role in the regulation of parathyroid cell proliferation and functions, particularly in PTH synthesis and secretion. A reduced CaR expression level has been reported in the parathyroid cells of patients and rats with SHPT (2)(3)(4)(5)7,19,20). These observations support the hypothesis that CaR downregulation is attributed to the high proliferative activity of parathyroid cells in primary hyperparathyroidism and SHPT.…”

Section: Discussionsupporting

confidence: 75%

“…CaR has been suggested to play an important role in pathologic parathyroid hyperplastic disorders (7,12,19 -26). There are some reports that a decreased CaR level is observed in the hyperplastic parathyroid glands of uremic rats that are fed an HP diet (7,19,20). It was shown that a decreased CaR expression level is observed particularly in a lesion with an increased number of PCNA-positive cells in the hyperplastic parathyroid glands of uremic rats (19).…”

Section: Discussionmentioning

confidence: 99%

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Calcimimetic Compound Upregulates Decreased Calcium-Sensing Receptor Expression Level in Parathyroid Glands of Rats with Chronic Renal Insufficiency

Mizobuchi¹,

Hatamura

Ogata

et al. 2004

Journal of the American Society of Nephrology

104

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Abstract.The reduced expression level of the calcium-sensing receptor (CaR) is attributed to the hyposensitivity of parathyroid cells to extracellular calcium concentration [Ca 2ϩ ]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 ϭ 12; Nx-8 group) or 9 wk (n ϭ 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 mol/kg body wt) once a day for 7 d (n ϭ 11; NxϩR-568 group). Sham-operated rats that were fed a standard diet for 9 wk were used as controls (n ϭ 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 NxϩR-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 NxϩR-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 [Ca 2ϩ ]o.The parathyroid hormone (PTH) plays a critical role in calcium (Ca) homeostasis and bone mineral metabolism. PTH secretion from parathyroid gland cells is closely regulated by several factors, including serum Ca and phosphorus (P) levels. The calcium-sensing receptor (CaR) on the parathyroid cell surface senses extracellular Ca concentration ([Ca 2ϩ ]o) accurately and mediates PTH synthesis and PTH secretion with other factors, including P and vitamin D (1). It has been reported that the expression levels of the CaR gene and CaR protein are reduced in the parathyroid glands of patients with primary or secondary hyperparathyroidism (SHPT), in which PTH is oversecreted despite normal or high [Ca 2ϩ ]o (2-5). The mechanism underlying the regulation ...

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Calcimimetic Compound Upregulates Decreased Calcium-Sensing Receptor Expression Level in Parathyroid Glands of Rats with Chronic Renal Insufficiency

Mizobuchi¹,

Hatamura

Ogata

et al. 2004

Journal of the American Society of Nephrology

104

View full text Add to dashboard Cite

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“…Our results confirm a decrease in CaR in the course of 2 HPT. However, as previously reported (Ritter et al 2001) the reduction in CaR expression occurs early in the course of 2 HPT (before the set point begins to increase); thus, other factors related to parathyroid hyperplasia may also influence the increase in the set point detected with the progression of 2 HPT.…”

Section: Discussionmentioning

confidence: 50%

The influence of the progression of secondary hyperparathyroidism on the set point of the parathyroid hormone-calcium curve

Bas

Aguilera–Tejero

Bas³

et al. 2005

Journal of Endocrinology

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The influence of secondary hyperparathyroidism (2 HPT) on the set point of the parathyroid hormone (PTH)-Ca 2+ curve is controversial. In vitro experiments have shown an increase in the set point. However, clinical studies with hemodialysis patients have provided a variety of results (increases, decreases and no changes in the set point have been reported). The present study was designed to investigate the influence of the progression of 2 HPT on the set point of the PTH-Ca 2+ curve. The PTH-Ca 2+ curve and the expression of parathyroid calcium receptor (CaR mRNA) and vitamin D receptor (VDR mRNA) have been studied in normal rabbits (group I, n=9) and in nephrectomized rabbits (group II, n=18) at two stages after inducing 2 HPT: 2-3 weeks (group IIA) and 5-6 weeks (group IIB). In group I, the set point of the PTH-Ca 2+ curve was 1·63 0·03 mM. A progressive hypocalcemia was detected during the evolution of 2 HPT (groups IIA and IIB). Rabbits from group IIA had a significant (P<0·001) decrease in the set point to values of 1·45 0·02 mM. However, the set point increased significantly in group IIB (P<0·001) to 1·56 0·03 mM. CaR mRNA was similarly decreased in groups IIA (39 12%) and IIB (48 7%). No changes were detected in VDR mRNA. In conclusion, a reduction in the set point of the PTH-Ca 2+ curve in response to decreased extracellular Ca 2+ was detected in the early phases of 2 HPT. However, with the progression of 2 HPT the set point tended to increase even though extracellular Ca 2+ was markedly decreased. The increase in the set point in the course of 2 HPT seems to be a complex process that cannot be fully explained by changes in parathyroid CaR mRNA or VDR mRNA.

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“…As such, it is not clear whether the proliferation of the parathyroid cells is the consequence of a downregulated expression of the CaR or whether there are decreased levels of the CaR because the parathyroid cells are proliferating rapidly and proliferating cells lack a well-formed CaR. Recent reports indicate that the proliferation of the PG may precede the downregulation of the CaR (22,23). In this study, we did not examine whether the parathyroid cell proliferation was inhibited after reversal of uremia.…”

Section: Discussionmentioning

confidence: 87%

Persistent Downregulation of Calcium-Sensing Receptor mRNA in Rat Parathyroids when Severe Secondary Hyperparathyroidism Is Reversed by an Isogenic Kidney Transplantation

Lewin¹,

Garfia

Recio

et al. 2002

Journal of the American Society of Nephrology

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Abstract. Experimental severe secondary hyperparathyroidism (HPT) is reversed within 1 wk after reversal of uremia by an isogenic kidney transplantation (KT) in the uremic rats. Abnormal parathyroid hormone (PTH) secretion in uremia is related to downregulation of CaR and vitamin D receptor (VDR) in the parathyroid glands (PG). The aim of this investigation was to examine the expression of CaR and VDR genes after reversal of uremia and HPT in KT rats. 5/6 nephrectomized rats were kept on a normal or high-phosphorus (hP) diet for 8 wk to induce severe HPT (n ϭ 8 in each group). In another group of seven uremic hP rats, uremia was reversed by an isogenic KT and PG were harvested within 1 wk posttransplant. Plasma urea, creatinine, total calcium, phosphorus, and PTH levels were measured. Parathyroid CaR and VDR mRNA were measured by quantitative PCR. Uremic hP rats had significantly elevated levels of creatinine, urea, and phosphorus (P Ͻ 0.001) and developed significant hypocalcemia (plasma calcium 1.83 Ϯ 0.2 mmol/L; P Ͻ 0.001) compared with normal control rats. After KT, the levels were normalized from day 3 to 7: creatinine from 0.117 Ϯ 0.016 to 0.050 Ϯ 0.002 mmol/L; urea from 23 Ϯ 4 to 7 Ϯ 0.3 mmol/L; phosphorus from 3.9 Ϯ 0.6 to 1.5 Ϯ 0.06 mmol/L; calcium from 1.8 Ϯ 0.2 to 2.5 Ϯ 0.02 mmol/L. Plasma PTH levels fell from 849 Ϯ 224 to a normal level of 38 Ϯ 9 pg/ml (P Ͻ 0.01). In uremic rats on a standard diet, CaR mRNA was similar to that of normal control rats, whereas VDR mRNA was significantly decreased. In uremic rats kept on hP diet, CaR mRNA was significantly decreased to 26 Ϯ 7% of control rats (P ϭ 0.01) and VDR mRNA reduced to 36 Ϯ 11% (P Ͻ 0.01). In KT, previously hP uremic rats, both CaR mRNA and VDR mRNA remained severely reduced (CaR, 39 Ϯ 7%; VDR, 9 Ϯ 3%; P Ͻ 0.01) compared with normal rats. In conclusion, circulating plasma PTH levels normalized rapidly after KT, despite persisting downregulation of CaR and VDR gene expression. This indicates that upregulation of CaR mRNA and VDR mRNA is not necessary to induce the rapid normalization of PTH secretion from hyperplastic parathyroid glands.In chronic uremia, the parathyroid gland (PG) function is abnormal, resulting in an increase in parathyroid hormone (PTH) biosynthesis and secretion and parathyroid cell hyperplasia (1,2,3). The molecular basis for the abnormal PTH secretion still remains partly obscure. It presumably involves dysfunction of the mechanism by which the parathyroid cells sense changes in plasma calcium (4). PG from patients with severe secondary or tertiary hyperparathyroidism (HPT) have an elevated set-point for Ca ϩϩ in vitro (5). A substantial reduction in the expression of the Ca ϩϩ -sensing receptor (CaR) protein and mRNA has been demonstrated in hyperplastic parathyroid glands from uremic patients (6,7). 1,25(OH) 2 D 3 dramatically decreases PTH gene transcription (8), and it has been proposed that this sterol also influences the sensitivity of the parathyroid cells to Ca ϩϩ (9). Changes in the vitamin D receptor (VDR) concent...

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Parathyroid hyperplasia in uremic rats precedes down-regulation of the calcium receptor

Abstract: These data indicate that parathyroid cell hyperplasia precedes down-regulation of CaR expression in the uremic rat model.

Cited by 100 publications

References 23 publications

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

The influence of the progression of secondary hyperparathyroidism on the set point of the parathyroid hormone-calcium curve

Persistent Downregulation of Calcium-Sensing Receptor mRNA in Rat Parathyroids when Severe Secondary Hyperparathyroidism Is Reversed by an Isogenic Kidney Transplantation

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