The calcimimetic compound NPS R-568 suppresses parathyroid cell proliferation in rats with renal insufficiency. Control of parathyroid cell growth via a calcium receptor.

Wada, Michihito; Furuya, Y; Sakiyama, Jun Ichi; Kobayashi, Nobuhiko; Miyata, Sonoe; Ishii, Hiromi; Nagano, Nobuo

doi:10.1172/jci119851

Cited by 242 publications

(176 citation statements)

References 31 publications

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“…Calcimimetics are undoubtedly promising agents, with the potential to abrogate hyperparathyroidism (63), parathyroid hyperplasia (22,63), and bone disease (17,64) in renal failure. The present data further suggest that the benefit from calcimimetics may extend beyond classical target organs of PTH.…”

Section: Discussionmentioning

confidence: 99%

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Beneficial Effects of Calcimimetics on Progression of Renal Failure and Cardiovascular Risk Factors

Ogata¹,

Ritz²,

Odoni³

et al. 2003

Journal of the American Society of Nephrology

139

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Abstract. In renal failure, parathyroid hormone (PTH) is not only involved in the genesis of disturbed calcium/phosphate metabolism and ostitis fibrosa; it is also a permissive factor in the genesis of hypertension, cardiovascular damage, and dyslipidemia. The allosteric activator of the calcium sensing receptor NPSR-568 (R-568) has been shown to reduce the serum intact PTH (iPTH) concentration in uremic rats. It was the purpose of this study in subtotally nephrectomized (SNX) rats to compare pharmacologic abrogation of secondary hyperparathyroidism by R-568 with parathyroidectomy (PTX). The effects on progression of renal failure, BP, and lipid and structural parameters of kidney and heart were studied. Four groups of male SD-rats were studied: (1) sham-operated ϩ vehicletreated rats (controls); (2) SNX ϩ vehicle-treated rats (SNX); (3) parathyroidectomized SNX ϩ vehicle-treated rats (SNXϩPTX); and (4) SNX ϩ calcimimetic R-568 -treated rats (SNXϩR-568). R-568 (50 mol/kg per d) was administered by gavage. Eight weeks after SNX, serum creatinine concentration, urinary albumin excretion, BP, and serum LDL-cholesterol concentration were significantly lower in both R-568 -treated and parathyroidectomized SNX compared with vehicletreated SNX. In addition, structural abnormalities of the kidney (glomerulosclerosis, tubulointerstitial changes) and the heart (interstitial fibrosis, capillary length density, arteriolar wall thickness) were significantly less pronounced than in vehicletreated SNX. It is concluded that in experimental renal failure abrogation of hyperparathyroidism by administration of a calcimimetic or PTX similarly attenuates progression of renal failure. Furthermore, it interferes with the development of cardiovascular risk factors and cardiac remodeling.Secondary hyperparathyroidism (sHPT) is a known complication of chronic renal failure. Elevated concentrations of parathyroid hormone (PTH) play a role not only in the pathogenesis of renal bone disease (1,2), but also in the development of cardiovascular risk factors such as disturbed lipid metabolism (3,4), glucose intolerance (5), and hypertension (6 -8). Parathyroidectomy (PTX) attenuates progression of renal failure in subtotally nephrectomized rats (SNX) on a high protein (9) or high phosphate (10,11) diet. sHPT is also known to play an important role in the development of structural abnormalities of the heart in renal failure, including left ventricular hypertrophy, interstitial fibrosis, and arteriolar wall thickening of the heart (7,(12)(13)(14).Allosteric activators of the calcium sensing receptor, e.g., NPSR-568 (R-568), reduce PTH secretion in rats or patients with primary and secondary hyperparathyroidism (15-20).There is no information on whether calcimimetics also affect abnormalities of uremia other than calcemia, phosphatemia (21), PTH concentrations (22), and skeletal abnormalities (17).Therefore, it was the purpose of this study to compare the effects of the calcimimetic R-568 and of parathyroidectomy on progression of renal failure, ...

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Section: Discussionmentioning

confidence: 99%

“…There is no information on whether calcimimetics also affect abnormalities of uremia other than calcemia, phosphatemia (21), PTH concentrations (22), and skeletal abnormalities (17).…”

mentioning

confidence: 99%

Beneficial Effects of Calcimimetics on Progression of Renal Failure and Cardiovascular Risk Factors

Ogata¹,

Ritz²,

Odoni³

et al. 2003

Journal of the American Society of Nephrology

139

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“…A linkage between the CaR and parathyroid cell proliferation in uremia has been suggested. This is based on the finding that the calcimimetic compound, NPS R-568, by acting directly on the CaR inhibited parathyroid cell proliferation in rats with renal insufficiency (21). It remains unclear, however, which are the molecular mechanisms that are involved in the CaRregulated parathyroid cell proliferation in uremia.…”

Section: Discussionmentioning

confidence: 99%

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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“…This leads to less suppression of PTH secretion and hence higher PTH levels. Because calcimimetics suppresses proliferation of parathyroid cells (24), it is possible that the reduction of CaSR expression also has stimulatory effects on parathyroid cell growth. Thus, derangement of CaSR expression may explain the two main characteristics of parathyroid adenoma, a higher set point for PTH secretion and enhancement of cell proliferation.…”

Section: Figmentioning

confidence: 99%

Cloning and Characterization of Two Promoters for the Human Calcium-sensing Receptor (CaSR) and Changes of CaSR Expression in Parathyroid Adenomas

Chikatsu¹,

Fukumoto²,

Takeuchi³

et al. 2000

Journal of Biological Chemistry

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Histological analyses showed that expression of the parathyroid calcium-sensing receptor (CaSR) is decreased in parathyroid adenomas. Because reduced expression of CaSR may result in insufficient suppression of parathyroid hormone secretion, the elucidation of regulatory mechanisms of CaSR expression is indispensable for understanding the pathogenesis of parathyroid adenomas. Two cDNA clones for human CaSR with different 5-untranslated regions have been isolated. However, the structure of the promoter region of human CaSR and the mechanisms of production of multiple CaSR mRNAs are unknown. We have cloned promoter regions of human CaSR by screening a genomic library. The human CaSR gene has two promoters and two 5-untranslated exons (exons 1A and 1B), and alternative usage of these exons leads to production of multiple CaSR mRNAs. The upstream promoter has TATA and CAAT boxes, and the downstream promoter is GC-rich. Northern blot analysis showed that expression levels of exon 1A in parathyroid adenomas are significantly less than those in normal glands. However, expression of exon 1B was not different between adenomas and normal glands. Thus, specific reduction of the transcript driven by the upstream promoter was observed in parathyroid adenomas. Further analyses of factors that modulate the activity of the upstream promoter are necessary to clarify the pathogenesis of parathyroid adenomas.

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The calcimimetic compound NPS R-568 suppresses parathyroid cell proliferation in rats with renal insufficiency. Control of parathyroid cell growth via a calcium receptor.

Cited by 242 publications

References 31 publications

Beneficial Effects of Calcimimetics on Progression of Renal Failure and Cardiovascular Risk Factors

Beneficial Effects of Calcimimetics on Progression of Renal Failure and Cardiovascular Risk Factors

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

Cloning and Characterization of Two Promoters for the Human Calcium-sensing Receptor (CaSR) and Changes of CaSR Expression in Parathyroid Adenomas

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