Calcitonin stimulation of renal 25-hydroxyvitamin D-1 alpha-hydroxylase activity in hypophosphatemic mice. Evidence that the regulation of calcitriol production is not universally abnormal in X-linked hypophosphatemia.

Nesbitt, Teresa; Lobaugh, Bruce; Drezner, Marc K.

doi:10.1172/jci112776

Cited by 40 publications

(11 citation statements)

References 26 publications

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“…Nevertheless, since studies in the Hyp mouse have documented that the deranged renal enzyme activity is likely localized to the proximal convoluted tubule, the site of defective phosphate transport, the causes of these abnormalities are undoubtedly linked. Indeed, currently available evidence (31)(32)(33) suggests that the enzyme dysfunction is an acquired defect secondary to this abnormality. Thus, the apparent hormonal/metabolic defect in Hyp mice most likely indirectly influences the expressed defect in calcitriol production.…”

Section: Discussionmentioning

confidence: 99%

Crosstransplantation of kidneys in normal and Hyp mice. Evidence that the Hyp mouse phenotype is unrelated to an intrinsic renal defect.

Nesbitt¹,

Coffman²,

Griffiths³

et al. 1992

J. Clin. Invest.

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209

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Although deranged phosphate transport is the fundamental abnormality in X-linked hypophosphatemic (XLH) rickets, it remains unknown if this defect is the consequence of an intrinsic kidney abnormality or aberrant production of a humoral factor. To discriminate between these possibilities, we examined phosphate homeostasis in normal and Hyp mice, subjected to renal crosstransplantation. We initially evaluated the effects of uninephrectomy on the indices of phosphate metabolism that identify the mutant biochemical phenotype. No

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Section: Discussionmentioning

confidence: 99%

Crosstransplantation of kidneys in normal and Hyp mice. Evidence that the Hyp mouse phenotype is unrelated to an intrinsic renal defect.

Nesbitt¹,

Coffman²,

Griffiths³

et al. 1992

J. Clin. Invest.

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209

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“…Indeed, studies in Hyp mice have established such defective regulation and indicate that the abnormal function is confined to a P/PTH-responsive enzyme that may be localized to the proximal convoluted tubule (PCT; 10,11,23), the site of the abnormal phosphate transport (24)(25)(26) characteristic of the disorder. While anatomic evidence for enzyme localization has not been obtained in the mouse as it has in the rat (27,28) and fetal rabbit (29), these observations do suggest that the aberrant vitamin D metabolism in XLH is probably an acquired defect dependent on the disturbance in phosphate transport and consequent alterations of the intracellular milieu (23,30). Therefore, the recent observation that altered renal P transport in Hyp and Gy mice is due to independent mutations in a family of genes on the X chromosome (9) raises significant questions regarding the ubiquity ofthe acquired defect in vitamin D metabolism in these genetic variants of the hypophosphatemic disorder.…”

Section: Discussionmentioning

confidence: 99%

Normal regulation of calcitriol production in Gy mice. Evidence for biochemical heterogeneity in the X-linked hypophosphatemic diseases.

Davidai¹,

Nesbitt²,

Drezner³

1990

J. Clin. Invest.

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Phenotypic heterogeneity in X-linked hypophosphatemic rickets (XLH) is ascribed to variable penetrance of the genetic abnormality. However (4.7±0.3 mg/dl) and phosphate (P)-depleted mice (4.9±0.4) was significantly less than normal (8.4±0.5). Consistent with P depletion, the Gy mice exhibited enhanced renal 25(OH)Dla-hydroxylase activity (9.3±0.6 fmol/mg kidney per min), similar to that of P-depleted normals (9.1±1.5), but significantly greater than that of controls (3.1±0.3). Such normal enzyme responsiveness was confirmed upon PTH stimulation (1 IU/h s.c.), which revealed that Gy mice increased renal 1-hydroxylase (59±7.7) similarly to normals (65±7.7) and Pdepleted animals (58.4±7.8). Calcitonin administration also enhanced enzyme function comparably in the animal models. Evidence confirming normally responsive calcitriol production in untreated Gy mice included increased serum 1,25-dihydroxyvitamin D levels, gastrointestinal calcium absorption, and urinary calcium. The normally regulated vitamin D metabolism in Gy mice indicates that biochemically diverse disease may result from mutations in the gene family regulating renal P transport and underlying X-linked hypophosphatemia. We suspect such heterogeneity is due to altered P transport at variable segments of the proximal convoluted tubule. (J. Clin. Invest. 1990. 85:334-339.) calcitriol -hypophosphatemia.

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“…Nishioka et al (33) provided evidence that CT plays a role in the postnatal increase of serum 1␣,25(OH) 2 D 3 . Nesbitt et al also reported that CT stimulated renal CYP27B1 activity in hypophosphatemic mice whose serum Ca level was within the normal range (34).…”

Section: Figmentioning

confidence: 96%

Calcitonin is a major regulator for the expression of renal 25-hydroxyvitamin D ₃ -1α-hydroxylase gene in normocalcemic rats

Shinki

Ueno

DeLuca

et al. 1999

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

130

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Regulation of vitamin D metabolism has long been examined by using vitamin D-deficient hypocalcemic animals. We previously reported that, in a rat model of chronic hyperparathyroidism, expression of 25-hydroxyvitamin D 3 -1␣-hydroxylase (CYP27B1) mRNA was markedly increased in renal proximal convoluted tubules. It is believed that the major regulator for the expression of renal CYP27B1 is parathyroid hormone (PTH). However, in the normocalcemic state, the mechanism to regulate the renal CYP27B1 gene could be different, since plasma levels of PTH are very low. In the present study, the effect of PTH and calcitonin (CT) on the expression of renal CYP27B1 mRNA was investigated in normocalcemic sham-operated rats and normocalcemic thy- 1-3). Furthermore, renal CYP27B1 activity was strongly inhibited by the administration of 1␣,25(OH) 2 D 3 . Thus, it is suggested that the renal CYP27B1 activity is regulated mainly by a balance of the serum levels of 1␣,25(OH) 2 D 3 and PTH.Another calcium-regulating hormone, calcitonin (CT), was also shown to enhance renal conversion of 25(OH)D 3 into 1␣,25(OH) 2 D 3 in vitamin D-deficient rats (5-7). Lorenc et al. (6), however, showed that CT did not exhibit any effect on vitamin D metabolism, when animals were thyroparathyroidectomized (TPTX). From these results, they concluded that the stimulatory effect of CT was mediated by the endogenous secretion of PTH. The effect of CT on the 1␣,25(OH) 2 D 3 synthesis and its interaction with PTH are of considerable interest, since the stimulatory effect of PTH on 1␣,25(OH) 2 D 3 synthesis appears to be mediated by cAMP (4), and CT also stimulates cAMP production in the kidney, irrespective of the counteracting effect of CT on PTH in maintaining plasma calcium homeostasis (8).It is believed that 1␣,25(OH) 2 D 3 is responsible for inducing most of the biological functions of vitamin D 3 (1-3). Theoretically, derangements in the tissue and plasma levels of 1␣,25(OH) 2 D 3 could result from alterations in the rate of its synthesis or degradation or both. Recently, four laboratories independently succeeded in the molecular cloning of the cDNA for CYP27B1 (9-13). The cloning of the CYP27B1 cDNA has enabled us to examine the expression of mRNA of this enzyme. Using this probe, we found that the expression of CYP27B1 mRNA was greatly increased in the kidney of vitamin D-deficient rats. In rats with the enhanced production of 1␣,25(OH) 2 D 3 , expression of CYP27B1 mRNA was also greatly stimulated in renal proximal convoluted tubules (9). Brenza et al. (14) and Murayama et al. (15) also reported that a PTH-dependent positive regulatory element for the CYP27B1 gene expression is located in the promoter region of the gene.Regulation of vitamin D metabolism has long been examined by using hypocalcemic or hypophosphatemic vitamin D-deficient animals. It was difficult to examine the regulation of CYP27B1 activity in normocalcemic physiological conditions. 1␣,25(OH) 2 D 3 has been characterized as a negative regulator for the activity of renal...

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Calcitonin stimulation of renal 25-hydroxyvitamin D-1 alpha-hydroxylase activity in hypophosphatemic mice. Evidence that the regulation of calcitriol production is not universally abnormal in X-linked hypophosphatemia.

Abstract: Hypophosphatemia (Hyp)

Cited by 40 publications

References 26 publications

Crosstransplantation of kidneys in normal and Hyp mice. Evidence that the Hyp mouse phenotype is unrelated to an intrinsic renal defect.

Crosstransplantation of kidneys in normal and Hyp mice. Evidence that the Hyp mouse phenotype is unrelated to an intrinsic renal defect.

Normal regulation of calcitriol production in Gy mice. Evidence for biochemical heterogeneity in the X-linked hypophosphatemic diseases.

Calcitonin is a major regulator for the expression of renal 25-hydroxyvitamin D ₃ -1α-hydroxylase gene in normocalcemic rats

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Calcitonin stimulation of renal 25-hydroxyvitamin D-1 alpha-hydroxylase activity in hypophosphatemic mice. Evidence that the regulation of calcitriol production is not universally abnormal in X-linked hypophosphatemia.

Abstract: Hypophosphatemia (Hyp)

Cited by 40 publications

References 26 publications

Crosstransplantation of kidneys in normal and Hyp mice. Evidence that the Hyp mouse phenotype is unrelated to an intrinsic renal defect.

Crosstransplantation of kidneys in normal and Hyp mice. Evidence that the Hyp mouse phenotype is unrelated to an intrinsic renal defect.

Normal regulation of calcitriol production in Gy mice. Evidence for biochemical heterogeneity in the X-linked hypophosphatemic diseases.

Calcitonin is a major regulator for the expression of renal 25-hydroxyvitamin D 3 -1α-hydroxylase gene in normocalcemic rats

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Calcitonin is a major regulator for the expression of renal 25-hydroxyvitamin D ₃ -1α-hydroxylase gene in normocalcemic rats