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PubMed2004

Phosphatonin washout in Hyp mice proximal tubules: evidence for posttranscriptional regulation.

X-linked hypophosphatemia is the most common inherited form of rickets. It is characterized by renal phosphate wasting, leading to hypophosphatemia and an inappropriately normal or low serum level of 1,25(OH)2 vitamin D. Previous studies have pointed to a circulating factor or phosphatonin-inhibiting phosphate transport by decreasing mRNA of the proximal tubule NaP(i) cotransporter NaPi-2A. The present study examined the hypothesis that there was also posttranscriptional regulation of the NaPi-2A cotransporter in Hyp mice proximal tubules and whether the phosphate transport defect in Hyp mice persisted when they were studied in vitro. We found that the rate of phosphate transport in Hyp mice was <50% that in C57/B6 control mice. While phosphate transport remained stable during incubation with time in C57/B6 mice proximal tubules, it increased from 0.46 +/- 0.47 to 1.83 +/- 0.40 pmol x mm(-1) x min(-1) in Hyp proximal tubules (P < 0.01) consistent with phosphatonin washout in Hyp proximal tubules perfused in vitro. This time-dependent increase in phosphate transport was still observed in the presence of cycloheximide. There was also a reduction of proximal tubule apical NaPi-2A expression from Hyp mice compared with C57/B6 mice using single-tubule immunohistochemistry. Using immunohistochemistry, we demonstrate an increase in apical expression of the NaPi-2A transporter in proximal tubules perfused in vitro in Hyp mice even in the presence of bath cycloheximide. The increase in apical expression of the NaPi-2A transporter in proximal tubules perfused in vitro in Hyp mice was blocked by colchicine. These data are consistent with a rapidly reversible posttranscriptional defect in Hyp mice causing a reduction in phosphate transport.

Adsorption↗

PubMed2005

Fibroblast growth factor-23 increases mouse PGE2 production in vivo and in vitro.

Fibroblast growth factor-23 (FGF-23) has been implicated in the renal phosphate wasting in X-linked hypophosphatemia, tumor-induced osteomalacia, and autosomal dominant hypophosphatemic rickets. Recently, we demonstrated that Hyp mice have greater urinary PGE2 levels compared with C57/B6 mice and that indomethacin administration in vivo and in vitro ameliorates the phosphate transport defect in Hyp mice. To determine further whether altered prostaglandin metabolism plays a role in the renal phosphate transport defect in Hyp mice, we incubated renal proximal tubules with arachidonic acid. We find that PGE2 production was higher in Hyp mice than in C57/B6 mice. Incubation of C57/B6 mouse renal proximal tubules with FGF-23R176Q, an active mutant form of FGR23, increased tubular PGE2 production, an effect that was inhibited by 50 microM PD-98059 and 10 microM SB-203580, inhibitors of the MAP kinase pathway. C57/B6 mice injected with FGF-23R176Q had a approximately 10-fold increase in PGE2 excretion 24 h after intraperitoneal injection of FGF-23R176Q compared with vehicle-treated controls. Finally, we show that PGE2 inhibited both phosphate and volume absorption in mouse proximal convoluted tubules perfused in vitro and reduced brush-border membrane vesicle NaPi-2a protein abundance from renal cortex incubated in vitro with PGE2. In conclusion, FGF-23 increases urinary and renal tubular PGE2 production via the MAP kinase pathway and PGE2 inhibits proximal tubule phosphate transport.

Animals↗

PubMed1982

Abnormal tubular adaptation to dietary Pi restriction in X-linked hypophosphatemic mice.

The renal handling of inorganic phosphate (Pi) is in part under the control of a powerful mechanism that is independent of parathyroid hormone and has the ability to enhance net tubular Pi reabsorption in response to a reduction in the Pi supply. The decreased renal reabsorption of Pi, the salient feature of the human disease X-linked hypophosphatemia, could be due to a loss of this adaptive capability of the tubular Pi transport system. To investigate this hypothesis, mutant hypophosphatemic (HYP) mice were used as a model of the human disease. Male HYP mice and normal littermates were subjected to high (0.75 g/100 g), low (0.25 g/100 g), or very low (0.03 g/100 g) phosphorus diets for periods varying between 1 and 20 days. Then the overall tubular Pi transport capacity was assessed by determining the maximal net Pi reabsorption per unit volume of glomerular filtrate (max TRPi/ml GF). The results indicate that the marked enhancement of max TRPi/ml GF, which is observed in normal mice after the first day of Pi restriction, is completely absent in HYP mice. In chronically thyroparathyroidectomized animals, 10 days of low phosphorus diet stimulated conspicuous max TRPi/ml GF in normal mice, whereas the same regimen did not significantly change the Pi reabsorptive capacity of HYP counterparts. The results of this study suggest that X-linked hypophosphatemia is a disease with a defect in the mechanism responsible for the adaptation of the tubular Pi transport system to Pi restriction.

Animals↗

PubMed1991

Abnormal proximal tubule apical membrane protein composition in X-linked hypophosphatemic mice.

The hypophosphatemic (Hyp) mouse is characterized by an isolated X-linked defect in proximal tubular phosphate (Pi) reabsorption associated with a decreased maximum velocity (Vmax) and a normal affinity (Km). To directly investigate the underlying cellular defect proximal tubular brush-border membranes (BBM) from normal control (Con) and Hyp male littermates were examined for differences in cholesterol content, total and individual phospholipid composition, phospholipid incorporation rates, membrane fluidity, and by two-dimensional sodium dodecyl sulfate (SDS)-polyacrylamide protein electrophoresis. The cholesterol content, total and individual phospholipid profiles, phospholipid incorporation rates, and membrane fluidity of Con and Hyp BBM samples were comparable. However, the two-dimensional gel electrophoreses of Con and Hyp BBM proteins, run simultaneously under identical conditions, revealed a protein with an apparent abnormal isoelectric migration pattern in Hyp BBM samples. This protein had an apparent molecular weight 56,000 and an apparent pI of 7.2 and was consistently evident on Hyp gels (n = 3) but not on Con gels (n = 3). The appearance of this protein band was associated with a diminution in staining of a control protein of comparable apparent molecular weight but markedly lower apparent pI.

Animals↗

PubMed1995

X-linked hypophosphatemic rickets and the murine Hyp homologue.

Recent studies have reported the cloning of several sodium-dependent phosphate cotransport proteins from the apical membrane of proximal tubules of several species. The human proximal tubule apical sodium-phosphate cotransport protein maps to chromosome 5 in the 5q35 region, indicating that this gene is not a candidate for the genetic defect leading to X-linked hypophosphatemia (XLH). Studies in what is thought to be the murine XLH homologue, Hyp, also indicate that the proximal tubular phosphate cotransporter gene does not map to the X chromosome. In Hyp, message levels for the apical membrane sodium cotransport protein are reduced by approximately 50%, similar to the reductions in the apical membrane protein levels of the transporter. This indicates a potential transcriptional defect in Hyp, leading to underexpression of the sodium-dependent phosphate transport protein. Recent studies in the Hyp osteoblast have characterized the intrinsic abnormalities of the cell leading to the osteomalacia characteristic of both Hyp and XLH. These studies demonstrate that the Hyp osteoblast expresses normal rates of phosphate transport, but altered gluconeogenesis similar to the proximal tubule, and that there is an underphosphorylation of an important matrix protein, osteopontin. Since osteopontin is involved in matrix mineralization, defective posttranslational modification of the protein could be a factor in producing the osteomalacia of the Hyp. Other recent studies have demonstrated improved modalities of treatment for Hyp and potentially for XLH. These involve the use of phosphate and nonhypercalcemic analogues of 1 alpha,25-dihydroxyvitamin D3. Thus, although the detection of the genetic defect producing XLH and Hyp is awaited, significant advances in the characterization of the phenotype and the bone abnormalities continue.

Animals↗

PubMed2004

The genomic response of the mouse kidney to low-phosphate diet is altered in X-linked hypophosphatemia.

The mechanism for the renal adaptation to low-phosphate diets is not well understood. Whether the Hyp mutation of the Phex gene blocks this adaptation is also not clear. To gain further insight into this, 5-wk-old normal and Hyp mice were fed a control (1.0% P) or low-phosphate diet (0.03% P) for 3-5 days. Renal RNA was hybridized to Affymetrix U74Av2 microarrays (5 arrays/group). Of the 5,719 detectable genes on each array, 290 responded significantly (P < 0.01) to low-phosphate diet in normal mice. This was reduced significantly (P < 0.001) to 7 in the Hyp mice. This suggested that the adaptations of the normal kidney to a low-phosphate environment were blocked by the Hyp mutation. The Npt2 phosphate transporter, vitamin D 1alpha- and 24-hydroxylases, and calbindins D9K and D28K responded in the expected fashion. Genes with significant (P < 0.05) diet-by-genotype interaction were analyzed by GenMAPP and MAPPFinder. This revealed a cluster of differentially expressed genes associated with microtubule-based processes. Most alpha- and beta-tubulins and most kinesins had responses to low-phosphate diet in normal mice which were abolished or reversed in Hyp mice. In summary, renal adaptation to low-phosphate diet involved changes in the mRNA expression of specific genes. Disruption of these responses in Hyp mice may contribute to their abnormal phosphate homeostasis.

Adaptation, Physiological↗

PubMed2000

Hypophosphataemic rickets.

X-Linked hypophosphataemic rickets (XLH) is frequently associated with short stature even when conventional treatment (1, 25-dihydroxyvitamin D(3) or 1alpha-hydroxyvitamin D(3) plus inorganic phosphate salts) is administered for a long time. The pathogenesis of growth retardation is probably multifactorial. Affected patients usually show normal growth hormone (GH) secretion. In some poorly growing XLH patients, long-term GH treatment associated with conventional therapy improves linear growth. GH treatment also increases phosphate retention but this effect is transient.

Child↗

PubMed2001

Loss of renal phosphate wasting in a child with autosomal dominant hypophosphatemic rickets caused by a FGF23 mutation.

A girl with autosomal dominant hypophosphatemic rickets, presented with clinical, radiological and laboratory signs of rickets at the age of 11 months. She showed a good response to the treatment with low doses of oral phosphate and calcitriol. Surprisingly, she lost her renal phosphate wasting at the age of 8 years, indicating that the disturbed phosphate metabolism can be compensated by hormonal or other factors.

Administration, Oral↗

PubMed2002

Molecular genetics of vitamin D- dependent hereditary rickets.

Vitamin D exerts a wide variety of biological actions. The active form of vitamin D, 1alpha,25(OH)(2)D(3), is biosynthesized from cholesterol. The final, critical step in this biosynthesis is conversion from 25-hydroxyvitamin D(3) to 1alpha,25(OH)(2)D(3) by the enzyme 25-hydroxyvitamin D(3) 1alpha-hydroxylase(CYP27B1)[1alpha(OH)ase]. 1alpha,25(OH)(2)D(3) transcriptionally controls the expression of a particular set of target genes mediated through nuclear vitamin D receptor(VDR) acting as a ligand-inducible factor. Two types of vitamin D-dependent hereditary rickets (VDDR) are known to be caused by mutations in the 1alpha(OH)ase and VDR genes. The 1alpha(OH)ase gene is responsible for VDDR type I, and VDR for type II. Both of the diseases display an autosomal-recessive trait, but clinical features and response to administrated 1alpha,25(OH)(2)D(3) are distinct. The phenotypes of the gene KO mice deficient of 1alpha(OH)ase and VDR exhibited the clinical abnormalities observed in the VDDR patients.

Calcitriol↗

PubMed2003

Schimmelpenning-Feuerstein-Mims syndrome with hypophosphatemic rickets.

The Schimmelpenning-Feuerstein-Mims syndrome (SFM syndrome) is a rare and variable multisystem defect consisting of congenital, extensive linear nevus sebaceus and associated abnormalities in different neuroectodermal organ systems. We present the history of a 52-year-old female patient with disproportionate hyposomia and asymmetric constitution. From birth she suffered from a right-sided, extensive nevus sebaceus following Blaschko's lines extending on the scalp, neck, right arm and trunk. At the age of 5 years, she developed a generalized growth retardation, along with deformations of bones. At the age of 11, hypophosphatemic rickets was diagnosed causing this growth retardation. Moreover, the patient developed a precocious puberty at the age of 9 years. When we saw the patient 40 years after the diagnosis had been made, phosphaturia had returned to normal. Specific therapy of hypophosphatemic rickets is straightforward and efficient in preventing late complications like growth retardation. We suggest to conduct appropriate laboratory tests in early childhood in patients with an extensive systematized sebaceous nevus or with additional signs of growth retardation or skeletal involvement, in order to exclude hypophosphatemic rickets associated with SFM syndrome.

Abnormalities, Multiple↗

PubMed2002

The X chromosome deletion in HYP mice extends into the intergenic region but does not include the SAT gene downstream from Phex.

The murine Hyp mutation is a model for X-linked hypophosphatemia (XLH), the most prevalent form of inherited rickets in humans. Although mutations in the murine Phex gene and the human PHEX gene have been identified in both murine and human disorders, the extent of the Hyp deletion on the mouse X chromosome has not been delineated. In the present study we demonstrate that the Hyp deletion starts in the middle of Phex intron 15 and includes approximately 48 kb of the 3' region of the Phex gene and approximately 10 kb of intergenic sequence on the mouse X chromosome. In addition, we show that the Hyp deletion does not involve the downstream spermidine/spermine N1-acetyl transferase (Sat; formerly Ssat) gene and thus is not a contiguous gene deletion syndrome. Our data indicate that the Hyp mouse is a true homolog of XLH in humans and underscore the validity of this murine model in studies of XLH pathophysiology and for testing novel treatment modalities.

Acetyltransferases↗

PubMed2003