Diminished parathyroid 1,25(OH)2D3 receptors in experimental uremia

Merke, J.; Hügel, Ulrike; Zlotkowski, A; Szabó, András; Bommer, Jürgen; Mall, Gerhard; Ritz, Eberhard

doi:10.1038/ki.1987.216

Cited by 113 publications

(39 citation statements)

References 16 publications

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“…Early treatment with 1,25(OH)2D3 and calcium prevents the hyperparathyroidism and the bone disease (23)(24)(25), however established secondary hyperparathyroidism is very resistant to therapy. In both human and experimental chronic renal failure a decreased number of parathyroid 1,25(OH)2D3 receptors has been demonstrated (26)(27)(28), and immunoreactive PTH levels have been shown to decrease after large, repeated doses of 1,25(OH)2D3, and only minimally to increases in serum calcium (29). Those findings are similar to the results of the present study using a dietary model of secondary hyperparathyroidism where PTH mRNA levels decreased after repeated 1,25(OH)2D3 doses but not to increases in serum calcium.…”

Section: Resultsmentioning

confidence: 99%

Regulation of parathyroid hormone gene expression by hypocalcemia, hypercalcemia, and vitamin D in the rat.

Naveh-Many¹,

Silver²

1990

J. Clin. Invest.

203

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In vivo in the rat 1,25(OH)2D3 decreases and a low calcium increases PTH mRNA levels. We now report the effect of 3 and 8 wk of changes in dietary vitamin D and calcium on PTH mRNA levels. PTH mRNA levels were increased by 3 wk of calcium deficiency (five times), a vitamin D-deficient diet (two times), and combined deficiency (10 times), but not changed by high calcium. Vitamin D-deficient-diet rats' PTH mRNA did not decrease after a single large dose of 1,25(OH)2D3, but did decrease partially after repeated daily doses of 1,25(OH)2D3. Rats after a vitamin D-, calcium-deficient (-D-Ca) diet did not respond to changes in serum calcium at 1 h. Flow cytometry of isolated cells from parathyroid-thyroid tissue separated the smaller parathyroid from the larger thyroid cells and allowed an analysis of parathyroid cell number. In normal vitamin D/normal calcium (NDNCa) rats the parathyroid cells were 24.7±3.4% (n = 6) of the total cell number, whereas in -D-Ca rats they were 41.8±6.6% (n = 6) (P < 0.05). That is, -D-Ca rats had 1.7 times the number of cells, whereas they had 10 times the amount of PTH mRNA, indicating the major contribution (6 times) of increased PTH gene expression per cell. Moreover, a calcium-deficient, more so than a vitamin D-deficient diet, amplifies the expression of the PTH gene, and vitamin D is necessary for an intact response of PTH mRNA to 1,25(OH)2D3 or calcium. (J. Clin. Invest. 1990Invest. . 86:1313Invest. -1319

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Section: Resultsmentioning

confidence: 99%

Regulation of parathyroid hormone gene expression by hypocalcemia, hypercalcemia, and vitamin D in the rat.

Naveh-Many¹,

Silver²

1990

J. Clin. Invest.

203

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“…Cell extracts were prepared as described elsewhere (7,10,20). In brief, cell suspensions (1.5 X 107 cells/ml) were homogenized in 0.4 M KTED buffer (TED buffer supplemented with 0.4 M KC1).…”

Section: Assay Of Vdr Activitymentioning

confidence: 99%

Identification and regulation of 1,25-dihydroxyvitamin D3 receptor activity and biosynthesis of 1,25-dihydroxyvitamin D3. Studies in cultured bovine aortic endothelial cells and human dermal capillaries.

et al. 1989

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Because 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) has been shown to play roles in both proliferation and differentiation of novel target cells, the potential expression of 1,25(OH)2D3 receptor (VDR) activity was investigated in cultured bovine aortic endothelial cells (BAEC). Receptor binding assays performed on nuclear extracts of BAEC revealed a single class of specific, high-affinity VDR that displayed a 4.5-fold increase in maximal ligand binding (Nm.x) in rapidly proliferating BAEC compared with confluent, density-arrested cells. When confluent BAEC were incubated with activators of protein kinase C (PKC), N., increased 2.5-fold within 6-24 h and this upregulation was prevented by sphingosine, an inhibitor of PKC, as well as by actinomycin D or cycloheximide. Immunohistochemical visualization using a specific MAb disclosed nuclear localized VDR in venular and capillary endothelial cells of human skin biopsies, documenting the expression of VDR, in vivo, and validating the BAEC model. Finally, additional experiments indicated that BAEC formed the 1,25(OH)2D3 hormonal metabolite from 25(OH)D3 substrate, in vitro, and growth curves of BAEC maintained in the presence of 10-8 M 1,25(OH)2D3 showed a 36% decrease in saturation density. These data provide evidence for the presence of a vitamin D microendocrine system in endothelial cells, consisting of the VDR and a la-hydroxylase enzyme capable of producing 1,25(OH)2D3. That both components of this system are coordinately regulated, and that BAEC respond to the 1,25(OH)2D3 hormone by modulating growth kinetics, suggests the existence of a vitamin D autocrine loop in endothelium that may play a role in the development and/or functions of this pathophysiologically significant cell population. Introduction It is well established that 1,25-dihydroxyvitamin D3 (1,25(OH)2D3)' is a crucial hormone in Ca2' homeostasis (1). (13) and also is biosynthesized in several ofits peripheral target cells (4-6) in addition to the traditional renal site of formation. Because endothelial cells are a dynamic tissue with spontaneous or injury-dependent cell renewal and expression of specific cell functions at the blood/vessel-wall interface, these cells were examined to determine whether they are potential targets for 1,25(OH)2D3. Initially, the possible presence of specific binding sites for 1,25(OH)2D3 was probed using cultured bovine aortic endothelial cells (BAEC) as a model. When receptors for 1,25(OH)2D3 were observed, the following hypotheses were tested: (a) that the growth state of BAEC may be associated with changes in VDR activity; (b) that BAEC differentiation induced by activators of protein kinase C (PKC) (14-17) may be associated with VDR regulation; (c) that growth parameters of BAEC may be altered in response to 1,25(OH)2D3; (d) that the receptor may be expressed in vivo in endothelial cells in venules and capillaries of human skin; and (e) that BAEC may possess la-hydroxylase activity to form the sterol hormone ligand for the receptor. These studies describe the ...

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“…In experimental uremia in 5/6 nephrectomized rats, a significant HPT is induced, which becomes far more severe when the uremic rats are kept on a high-phosphorus (hP) diet (11,12). In such uremic HPT rat models, a reduced VDR mRNA has been demonstrated in the parathyroids by some investigators (13). A decrease of the CaR protein and mRNA expression has further been observed in the parathyroid glands of hyperphosphatemic uremic rats but not in uremic rats kept on standard diet (14).…”

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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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Diminished parathyroid 1,25(OH)2D3 receptors in experimental uremia

Cited by 113 publications

References 16 publications

Regulation of parathyroid hormone gene expression by hypocalcemia, hypercalcemia, and vitamin D in the rat.

Regulation of parathyroid hormone gene expression by hypocalcemia, hypercalcemia, and vitamin D in the rat.

Identification and regulation of 1,25-dihydroxyvitamin D3 receptor activity and biosynthesis of 1,25-dihydroxyvitamin D3. Studies in cultured bovine aortic endothelial cells and human dermal capillaries.

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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