Phosphate depletion in the rat: Effect of bisphosphonates and the calcemic response to PTH

Jara, Aquiles; Lee, Elizabeth; Stauber, Deborah J.; Moatamed, Farhad; Felsenfeld, Arnold J.

doi:10.1046/j.1523-1755.1999.00395.x

Cited by 22 publications

(18 citation statements)

References 52 publications

(9 reference statements)

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“…We then treated TPTX, PTH-supplemented rats with an antibone-resorptive agent (2.5 μg pamidronate.g BW -1 , daily for 4 days prior to the experiment); this treatment significantly inhibits bone resorption in rats and mice as validated in previous studies (9,12,13). As shown in Figure 4, at baseline, both groups of rats exhibited the same blood ionized Ca concentration and urinary Ca excretion.…”

Section: Figurementioning

confidence: 65%

PTH-independent regulation of blood calcium concentration by the calcium-sensing receptor

Loupy¹,

Ramakrishnan²,

Wootla³

et al. 2012

J. Clin. Invest.

178

171

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Tight regulation of calcium levels is required for many critical biological functions. The Ca 2+ -sensing receptor (CaSR) expressed by parathyroid cells controls blood calcium concentration by regulating parathyroid hormone (PTH) secretion. However, CaSR is also expressed in other organs, such as the kidney, but the importance of extraparathyroid CaSR in calcium metabolism remains unknown. Here, we investigated the role of extraparathyroid CaSR using thyroparathyroidectomized, PTH-supplemented rats. Chronic inhibition of CaSR selectively increased renal tubular calcium absorption and blood calcium concentration independent of PTH secretion change and without altering intestinal calcium absorption. CaSR inhibition increased blood calcium concentration in animals pretreated with a bisphosphonate, indicating that the increase did not result from release of bone calcium. Kidney CaSR was expressed primarily in the thick ascending limb of the loop of Henle (TAL). As measured by in vitro microperfusion of cortical TAL, CaSR inhibitors increased calcium reabsorption and paracellular pathway permeability but did not change NaCl reabsorption. We conclude that CaSR is a direct determinant of blood calcium concentration, independent of PTH, and modulates renal tubular calcium transport in the TAL via the permeability of the paracellular pathway. These findings suggest that CaSR inhibitors may provide a new specific treatment for disorders related to impaired PTH secretion, such as primary hypoparathyroidism.

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Section: Figurementioning

confidence: 65%

PTH-independent regulation of blood calcium concentration by the calcium-sensing receptor

Loupy¹,

Ramakrishnan²,

Wootla³

et al. 2012

J. Clin. Invest.

178

171

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“…Furthermore, histomorphometric analysis revealed that indexes of bone formation are increased and of bone resorption decreased in Npt2 Ϫ/Ϫ mice compared with wild-type littermates (10). This is clearly not the case in P i -depleted rats where several characteristics of bone, as measured by histomorphometry, are significantly compromised compared with P i -replete controls (12). Taken together, the data suggest that increased bone resorption is not a major contributor to the hypercalcemia and hypercalciuria in Npt2 Ϫ/Ϫ mice.…”

Section: Discussionmentioning

confidence: 75%

1α-Hydroxylase gene ablation and P_isupplementation inhibit renal calcification in mice homozygous for the disruptedNpt2agene

Tenenhouse¹,

Gauthier²,

Chau³

et al. 2004

American Journal of Physiology-Renal Physiology

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-Arnaud. 1␣-Hydroxylase gene ablation and P i supplementation inhibit renal calcification in mice homozygous for the disrupted Na-P i cotransporter gene Npt2a. Am J Physiol Renal Physiol 286: F675-F681, 2004. First published December 2, 2003 10.1152/ ajprenal.00362.2003.-Disruption of the major renal Na-phosphate (P i) cotransporter gene Npt2a in mice leads to a substantial decrease in renal brush-border membrane Na-P i cotransport, hypophosphatemia, and appropriate adaptive increases in renal 25-hydroxyvitamin D 3-1␣-hydroxylase (1␣OHase) activity and the serum concentration of 1,25-dihydroxyvitamin D3 [1,25(OH)2D]. The latter is associated with increased intestinal Ca absorption, hypercalcemia, hypercalciuria, and renal calcification in Npt2 Ϫ/Ϫ mice. To determine the contribution of elevated serum 1,25(OH) 2D levels to the development of hypercalciuria and nephrocalcinosis in Npt2 Ϫ/Ϫ mice, we examined the effects of 1␣OHase gene ablation and long-term Pi supplementation on urinary Ca excretion and renal calcification by microcomputed tomography. We show that the urinary Ca/creatinine ratio is significantly decreased in Npt2 Ϫ/Ϫ /1␣OHase Ϫ/Ϫ mice compared with Npt2 Ϫ/Ϫ mice. In addition, renal calcification, determined by estimating the calcified volume to total renal volume (CV/TV), is reduced by ϳ80% in Npt2 Ϫ/Ϫ /1␣OHase Ϫ/Ϫ mice compared with that in Npt2 Ϫ/Ϫ mice. In Npt2 Ϫ/Ϫ mice derived from dams fed a 1% Pi diet and maintained on the same diet, we observed a significant decrease in urinary Ca/creatinine that was also associated with ϳ80% reduction in CV/TV when compared with counterparts fed a 0.6% diet. Taken together, the present data demonstrate that both 1␣OHase gene ablation and P i supplementation inhibit renal calcification in Npt2 Ϫ/Ϫ mice and that 1,25(OH)2D is essential for the development of hypercalciuria and nephrocalcinosis in the mutant strain. phosphate wasting; hypophosphatemia; hypercalciuria; nephrocalcinosis; 1,25-dihydroxyvitamin D THE TYPE IIA Na-phosphate (P i ) cotransporter Npt2a is the most abundant Na-P i cotransporter in mouse kidney (23) and is expressed in the brush-border membrane (BBM) of proximal tubular cells (6) where the bulk of filtered P i is reabsorbed. Studies in our laboratory demonstrated that mice homozygous for the disrupted Npt2a gene (Npt2) exhibit an increase in urinary P i excretion, an ϳ80% loss in BBM Na-P i cotransport, and significant hypophosphatemia (2). In addition, Npt2 Ϫ/Ϫ mice fail to respond to P i deprivation with an adaptive increase in BBM Na-P i cotransport (11) and to parathyroid hormone (PTH) with a decrease in transport (27). These findings underscore the significant role of Npt2a in renal P i reabsorption and its regulation by dietary P i and PTH.Hypophosphatemia, induced by feeding a low-P i diet, is an important stimulus for increased renal synthesis of 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D] by the cytochrome P-450 25-hydroxyvitamin D 3 -1␣-hydroxylase (CYP27B1, hereafter referred to as 1␣OHase) (9). We showed that hypophosphatemi...

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“…It is modified by several factors. Phosphorus restriction and an increased serum calcitriol shift the EOP to the left (12)(13)(14) because less PTH is needed to maintain the same serum calcium concentration. Conversely, phosphorus loading, a deficiency of calcitriol, and renal failure shift the EOP to the right (15)(16)(17)(18)(19) because more PTH is needed to maintain the same serum calcium concentration.…”

Section: Bifunctional Relationship Between Pth and Serum Calciummentioning

confidence: 99%

“…Studies in normal and azotemic rats have shown that high dietary phosphate greatly increases PTH values (15,40). Conversely, dietary phosphate restriction reduces PTH values in normal rats and minimizes increases in PTH values in azotemic rats (13,41). Even in normal rats and humans who are given a single meal that contains a high phosphate content, it has been shown that postprandial PTH values increase (42)(43)(44).…”

Section: Basal Pthmentioning

confidence: 99%

Dynamics of Parathyroid Hormone Secretion in Health and Secondary Hyperparathyroidism

Felsenfeld

Rodríguez

Aguilera–Tejero

2007

Clinical Journal of the American Society of Nephrology

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This review examines the dynamics of parathyroid hormone secretion in health and in various causes of secondary hyperparathyroidism. Although most studies of parathyroid hormone and calcium have focused on the modification of parathyroid hormone secretion by serum calcium, the relationship between parathyroid hormone and serum calcium is bifunctional because parathyroid hormone also modifies serum calcium. In normal animals and humans, factors such as phosphorus and vitamin D modify the basal parathyroid hormone level and the maximal parathyroid hormone response to hypocalcemia. Certain medications, such as lithium and estrogen, in normal individuals and sustained changes in the serum calcium concentration in hemodialysis patients change the set point of calcium, which reflects the serum calcium concentration at which parathyroid hormone secretion responds. Hypocalcemia increases the basal/maximal parathyroid hormone ratio, a measure of the relative degree of parathyroid hormone stimulation. The phenomenon of hysteresis, defined as a different parathyroid hormone value for the same serum calcium concentration during the induction of and recovery from hypo-and hypercalcemia, is discussed because it provides important insights into factors that affect parathyroid hormone secretion. In three causes of secondary hyperparathyroidism-chronic kidney disease, vitamin D deficiency, and aging-factors that affect the dynamics of parathyroid hormone secretion are evaluated in detail. During recovery from vitamin D deficiency, the maximal parathyroid hormone remains elevated while the basal parathyroid hormone value rapidly becomes normal because of a shift in the set point of calcium. Much remains to be learned about the dynamics of parathyroid hormone secretion in health and secondary hyperparathyroidism. T his review examines the dynamics of parathyroid hormone (PTH) secretion in health and in various causes of secondary hyperparathyroidism with an emphasis on chronic kidney disease (CKD). For better understanding of factors that affect PTH secretion, the PTH-calcium relationship is evaluated with respect to (1) PTH secretion in the baseline state (basal PTH) and its sensitivity to the serum calcium concentration; (2) the maximal PTH response to hypocalcemia and factors that have been reported to modify the maximal PTH response to hypocalcemia; (3) shifts in the set point of calcium for PTH secretion in normal individuals as a result of treatment with medications such as lithium and estrogen and in hemodialysis patients during sustained changes in the serum calcium concentration; (4) the dynamics of PTH secretion in the secondary hyperparathyroidism of CKD, vitamin D deficiency, and aging; and (5) the phenomenon of hysteresis, defined as a different PTH value for the same serum calcium concentration during the induction of and recovery from both hypo-and hypercalcemia. A focus on hysteresis is justified because it provides important insights into how PTH secretion is modified by rate and directional changes in the serum c...

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Phosphate depletion in the rat: Effect of bisphosphonates and the calcemic response to PTH

Cited by 22 publications

References 52 publications

PTH-independent regulation of blood calcium concentration by the calcium-sensing receptor

PTH-independent regulation of blood calcium concentration by the calcium-sensing receptor

1α-Hydroxylase gene ablation and P_isupplementation inhibit renal calcification in mice homozygous for the disruptedNpt2agene

Dynamics of Parathyroid Hormone Secretion in Health and Secondary Hyperparathyroidism

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Phosphate depletion in the rat: Effect of bisphosphonates and the calcemic response to PTH

Cited by 22 publications

References 52 publications

PTH-independent regulation of blood calcium concentration by the calcium-sensing receptor

PTH-independent regulation of blood calcium concentration by the calcium-sensing receptor

1α-Hydroxylase gene ablation and Pisupplementation inhibit renal calcification in mice homozygous for the disruptedNpt2agene

Dynamics of Parathyroid Hormone Secretion in Health and Secondary Hyperparathyroidism

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1α-Hydroxylase gene ablation and P_isupplementation inhibit renal calcification in mice homozygous for the disruptedNpt2agene