Abnormal regulation of renal vitamin D catabolism by dietary phosphate in murine X-linked hypophosphatemic rickets.

Tenenhouse, Harriet S.; Jones, Glenville

doi:10.1172/jci114590

Cited by 63 publications

(46 citation statements)

References 25 publications

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“…In contrast to Pi-deprived Npt2 -/-mice, serum Pi in Pi-deprived Hyp mice is significantly lower than that in Pi-deprived normal mice (28,37,46 (33) retain the capacity to mount an adaptive increase in BBM Na + /Pi cotransport in response to low-Pi challenge (28,37). While the mechanism whereby loss of Phex function elicits the decrease in renal Npt2 gene expression is not understood, it is clear that, in contrast to Npt2, Phex is not necessary for the adaptive Na + /Pi cotransport response at the renal BBM.…”

Section: Figurementioning

confidence: 86%

Effects of Npt2 gene ablation and low-phosphate diet on renal Na+/phosphate cotransport and cotransporter gene expression

Hoag¹,

Martel²,

Gauthier³

et al. 1999

J. Clin. Invest.

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The renal Na + /phosphate (Pi) cotransporter Npt2 is expressed in the brush border membrane (BBM) of proximal tubular cells. We examined the effect of Npt2 gene knockout on age-dependent BBM Na + /Pi cotransport, expression of Na + /Pi cotransporter genes Npt1, Glvr-1, and Ram-1, and the adaptive response to chronic Pi deprivation. Na + /Pi cotransport declines with age in wild-type mice (Npt2 +/+ ), but not in mice homozygous for the disrupted Npt2 allele (Npt2 -/-). At all ages, Na + /Pi cotransport in Npt2 -/-mice is approximately 15% of that in Npt2 +/+ littermates. Only Npt1 mRNA abundance increases with age in Npt2 +/+ mice, whereas Npt1, Glvr-1, and Ram-1 mRNAs show an age-dependent increase in Npt2 -/-mice. Pi deprivation significantly increases Na + /Pi cotransport, Npt2 protein, and mRNA in Npt2 +/+ mice. In contrast, Pi-deprived Npt2 -/-mice fail to show the adaptive increase in transport despite exhibiting a fall in serum Pi. We conclude that (a) Npt2 is a major determinant of BBM Na + /Pi cotransport; (b) the age-dependent increase in Npt1, Glvr-1, and Ram-1 mRNAs in Npt2 -/-mice is insufficient to compensate for loss of Npt2; and (c) Npt2 is essential for the adaptive BBM Na + /Pi cotransport response to Pi deprivation.

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Section: Figurementioning

confidence: 86%

Effects of Npt2 gene ablation and low-phosphate diet on renal Na+/phosphate cotransport and cotransporter gene expression

Hoag¹,

Martel²,

Gauthier³

et al. 1999

J. Clin. Invest.

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“…The hypophosphatemia is caused by impaired proximal tubule phosphate reabsorption (1-6). The vitamin D deficiency is caused by decreased 25(OH)-vitamin D-1␣-hydroxylase activity (7)(8)(9)(10). Conventional therapy consists of oral administration of pharmacologic doses of vitamin D and phosphate, though hypercalciuria and nephrocalcinosis are frequent complications of such therapy (11)(12)(13)(14)(15).…”

mentioning

confidence: 99%

Correction of proximal tubule phosphate transport defect inHypmicein vivoandin vitrowith indomethacin

Baum

Loleh

Saini

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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X-linked hypophosphatemia is the most prevalent inherited form of rickets. In this disorder, rickets results from hyperphosphaturia and inappropriately normal levels of 1,25(OH) 2-vitamin D. Current therapy with oral phosphate and vitamin D improves the rickets, but has significant morbidity and does not significantly affect the short stature and hypophosphatemia. In the present study, we demonstrate that Hyp mice, which have a mutation homologous to that in patients with X-linked hypophosphatemia, have a 2-fold greater urinary prostaglandin E 2 (PGE2) excretion than C57͞B6 mice. To determine whether PGs were involved in the pathogenesis of this disorder, Hyp and C57͞B6 mice received i.p. injections with vehicle or indomethacin (1 mg͞kg of body weight twice daily for 4 days) and were studied Ϸ12 h after the last dose of indomethacin. In the Hyp mice, indomethacin treatment decreased the fractional excretion of phosphate from 13.0 ؎ 3.2% to 2.2 ؎ 1.1% (P < 0.05), and increased serum phosphate from 2.9 ؎ 0.2 mg͞dl to 4.1 ؎ 0.2 mg͞dl (P < 0.05). There was no effect of indomethacin in C57͞B6 mice. Indomethacin did not affect serum creatinine or inulin clearance, demonstrating that the normalization of urinary phosphate excretion was not caused by changes in glomerular filtration rate. Indomethacin treatment increased renal brush border membrane vesicle NaPi-2 protein abundance in Hyp mice to levels comparable to that of C57͞B6 mice, but had no effect in C57͞B6 mice. In vitro isolated perfused proximal tubule studies demonstrate directly that 10 ؊6 M bath indomethacin normalized the phosphate transport defect in Hyp mice but had no effect on C57͞B6 mice. In conclusion, there is dysregulation of renal PG metabolism in Hyp mice, and indomethacin treatment normalizes the urinary excretion of phosphate by a direct tubular effect.X-linked hypophosphatemia ͉ rickets ͉ sodium͞phosphate cotransporter NaPi-2

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“…In oncogenic osteomalacia there is evidence for inhibition of 25OHD 1-ahydroxylase (Drezner et al, 1982;Miyauchi et al, 1988) whereas in Hyp mice elevated catabolism of 1,25 (OH) 2 D due to increased activity of renal 25 (OH)D-24-hydroxylase (24-hydroxylase) has been shown. In Hyp mice, catabolism is further elevated following phosphate deprivation resulting in reduced concentrations of 1,25 (OH) 2 D (Tenenhouse & Jones, 1990).…”

Section: Differences Between Hyp and Oncogenic Osteomalaciamentioning

confidence: 99%

Oncogenic osteomalacia: is there a new phosphate regulating hormone?

Nelson

Robinson

Mason

1997

Clinical Endocrinology

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SummaryOncogenic osteomalacia is a syndrome associated with rare, usually mesenchymal tumours, which is characterized by hypophosphataemia, phosphaturia and low concentrations of 1,25-dihydroxyvitamin D. The reversal of clinical and biochemical abnormalities following removal of the tumour, indicates it is the source of a humoral factor that is responsible for these abnormalities. It has been demonstrated that the humoral factor inhibits renal phosphate uptake and reduces 1,25-dihydroxyvitamin D production. Although there is evidence that it may act via parathyroid hormone/parathyroid hormone-related peptide receptors and may be a peptide, the factor has not yet been identified, nor has its relationship to factors involved in X-linked hypophosphataemic rickets been established. We propose unifying hypotheses for the pathogenesis of oncogenic osteomalacia and X-linked hypophosphataemic rickets which involve defects in the PEX gene. These hypotheses do not fully explain all the available data and it remains possible that hormone(s) with little or no role in X-linked hypophosphataemic rickets may be responsible for oncogenic osteomalacia.

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Abnormal regulation of renal vitamin D catabolism by dietary phosphate in murine X-linked hypophosphatemic rickets.

Cited by 63 publications

References 25 publications

Effects of Npt2 gene ablation and low-phosphate diet on renal Na+/phosphate cotransport and cotransporter gene expression

Effects of Npt2 gene ablation and low-phosphate diet on renal Na+/phosphate cotransport and cotransporter gene expression

Correction of proximal tubule phosphate transport defect inHypmicein vivoandin vitrowith indomethacin

Oncogenic osteomalacia: is there a new phosphate regulating hormone?

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