Micropuncture study of renal phosphorus transport in hypophosphatemic vitamin D resistant rickets mice

Giasson, Suzanne D.; Brunette, Michèle G.; Danan, Gaby; Vigneault, Normand; Carrière, S; Fafard, Louis

doi:10.1007/bf00580769

Cited by 64 publications

(18 citation statements)

References 38 publications

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“…These studies demonstrated that immunofluorescence was restricted to the brush border membrane of both the proximal convoluted tubule, where the signal was strongest, and the proximal straight tubule, where a weaker signal was obtained ( 17). Based on these findings, it is likely that the Na'-Pi cotransporter protein that is reduced in Hyp mice is expressed in the brush border membrane of both proximal tubular segments, consistent with results of renal micropuncture studies in intact mice (8,9) and Pi transport measurements in isolated renal brush border membrane vesicles (6,7).…”

Section: Discussionsupporting

confidence: 80%

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Renal Na(+)-phosphate cotransport in murine X-linked hypophosphatemic rickets. Molecular characterization.

Tenenhouse¹,

Werner²,

Biber³

et al. 1994

J. Clin. Invest.

119

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The X-linked Hyp mouse is characterized by a specific defect in proximal tubular phosphate (Pi) reabsorption that is associated with a decrease in V .. of the high affinity Na+-Pi cotransport system in the renal brush border membrane. To understand the mechanism for V ,. reduction, we examined the effect of the Hyp mutation on renal expression of Na+-Pi cotransporter mRNA and protein. Northern hybridization of renal RNA with a rat, renal-specific Na+-Pi cotransporter cDNA probe (NaPi-2) (Magagnin et al. 1993. Proc. Nati. Acad. Sci. USA. 90:5979-5983.) demonstrated a reduction in a 2.6-kb transcript in kidneys of Hyp mice relative to normal littermates (NaPi-2/,B-actin mRNA = 57±6% of normal in Hyp mice, n = 6, P < 0.01). Na+-Pi cotransport, but not Na+-sulfate cotransport, was 50% lower in Xenopus oocytes injected with renal mRNA extracted from Hyp mice when compared with that from normal mice. Hybrid depletion experiments documented that the mRNA-dependent expression of Na+-Pi cotransport in oocytes was related to NaPi-2. Western analysis demonstrated that NaPi-2 protein is also significantly reduced in brush border membranes of Hyp mice when compared to normals. The present data demonstrate that the specific reduction in renal Na+-Pi cotransport in brush border membranes of Hyp mice can be ascribed to a proportionate decrease in the abundance of Na+-Pi cotransporter mRNA and protein. (J. Clin. Invest. 1994. 93:671-676.)

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Section: Discussionsupporting

confidence: 80%

“…The renal defect in Pi reabsorption in Hyp mice has been localized to the brush border membrane ofthe proximal tubule (6)(7)(8) and is not dependent on parathyroid hormone for its expression (9). Kinetic studies provided evidence for two distinct Na+-Pi cotransport systems in renal brush border membrane vesicles of Hyp mice (10).…”

Section: Introductionmentioning

confidence: 99%

Renal Na(+)-phosphate cotransport in murine X-linked hypophosphatemic rickets. Molecular characterization.

Tenenhouse¹,

Werner²,

Biber³

et al. 1994

J. Clin. Invest.

119

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“…Using micropuncture techniques, Giasson, Brunette, Danan, Vigneault & Carriere (1977) have suggested that there is a defect in phosphate transport in the kidney. Tenenhouse, Scriver, McInnes & Glorieux (1978) have provided evidence for a defect in the renal brush-border membrane.…”

Section: General Conclusion On Dwarf Micementioning

confidence: 99%

Mouse Mutants as Models in Endocrine Research

Charlton

1984

Exp Physiol

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Although Shire (1979) has listed some forty‐eight mouse mutants of interest to the endocrinologist, this short review has concentrated upon eleven mutations which have resulted in a significant number of scientific publications over the last 4 or 5 years. The selection of references has had to be limited, but it should be possible easily to expand the list given in this review. Although the proximate cause of none of the eleven mutations has been identified with certainty, the abnormalities of function have included hormone deficiencies and receptor and post‐receptor malfunctions. It is perhaps a reflexion on our society in the 1980s, that the bulk of research has concentrated on the obese mouse. However, we still do not know the initial cause of this syndrome. The major disadvantage of the mouse to the hormone assayist lies in the small blood volume and the extreme difficulty in taking serial blood samples over a short period of time. With increased sophistication of assay techniques this may prove less daunting, but is an area where a review of the literature reveals discrepancies between laboratories, and even between data generated by the same laboratory at different times. With regard to the hormone content of endocrine tissues, the way forward for peptide‐secreting glands may be in the measurement of mRNA levels for particular hormones. Certainly the methods of recombinant‐DNA technology will yield positive information upon the aetiology and expression of some of the syndromes considered above. Organ transplantation is an area in which mutant mice have proved useful, for example gonadal, pituitary and pancreatic tissue transplantation. The grafting of neural tissue in the hpg mouse has added a further dimension to this field of research. The great infrastructure of genetical research in mice has enabled us to breed mutant genes onto different genetic backgrounds. This area of research is one which deserves to expand. The techniues of in vitro fertilization, chimera formation and embryo transfer have been used, in part, in studies on mouse mutants, and should provide technical means for further investigating gene expression. The family of dwarf mutants are ideally suited for research into the expression of genes micro‐injected into the fertilized egg (see Charlton & Cox, 1983). As new hormones are isolated and become available for study these mouse mutants may well be useful in delineating physiological functions for natural and pharmacological products. Again, the dwarf mutants would seem ideally suited for research into the synthesis and action of GRF. Mouse mutants have proved of use to biochemists and embryologists and provide fertile ground for endocrine investigations ranging from molecular genetics to membrane biophysics.

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“…Phenotypic characteristics of XLH involve paradoxically low 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ] levels in response to hypophosphatemia, osteomalacia, rickets, and lower limb deformities that sometimes require surgery. The murine Hyp model reproduces these characteristics (15,18,48,49) and has been extensively used to study the cause of hypophosphatemia. In recent years it has become evident that the observed hypophosphatemia is not due to an intrinsic renal cell defect but results from humoral mediation (25).…”

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confidence: 99%

Role of abnormal neutral endopeptidase-like activities inHyp mouse bone cells in renal phosphate transport

Dubois

Ruchon

Delalandre

et al. 2002

American Journal of Physiology-Cell Physiology

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2002.-We investigated whether the absence of Phex (phosphate-regulating gene with homologies to endopeptidases on the X chromosome) in the Hyp mouse affects the expression and activity of neprilysin (NEP) and of endothelin-converting enzyme-like endopeptidase (ECEL1/DINE) in bone marrow stromal cells (BMSC) and osteoblasts (Ob). Total NEP-like activity was higher in Ob than in BMSC regardless of genotype, and Hyp cells showed higher activities than normal. Conditioned media (CM) from Hyp BMSC and Ob inhibited inorganic phosphate (Pi) uptake by mouse proximal tubule cells, and incubating Hyp Ob with phosphoramidon prevented the production of the inhibitor of renal P i uptake. A linear relationship was observed between the NEP-like activity of Hyp and normal cells and the inhibition of Pi uptake. NEP and ECEL1/DINE mRNA levels were higher in Hyp cells than in normal cells, and in situ hybridization of ECEL1/DINE confirmed higher levels of expression in the Hyp mouse than in normal cells. In conclusion, we observed a correlation between the inhibition of Pi uptake by CM from Hyp cells and elevated NEP-like activities.X-linked hypophosphatemia; Phex; putative inhibitor of renal phosphate uptake RENAL PHOSPHATE WASTING in human X-linked hypophosphatemia (XLH) is attributable to a specific reduction of phosphate (P i ) reabsorption in the proximal tubule (reviewed in Ref. 37). Phenotypic characteristics of XLH involve paradoxically low 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ] levels in response to hypophosphatemia, osteomalacia, rickets, and lower limb deformities that sometimes require surgery. The murine Hyp model reproduces these characteristics (15,18,48,49) and has been extensively used to study the cause of hypophosphatemia. In recent years it has become evident that the observed hypophosphatemia is not due to an intrinsic renal cell defect but results from humoral mediation (25). This hypothesis was first proposed by Meyer et al. (30) following the observation that parabiosis between a normal and a Hyp mouse results in progressive hypophosphatemia in the normal animal in association with a diminished renal reabsorption of phosphate. Kidney transplantation from normal to Hyp mice and from Hyp to normal mice and measurements of P i uptake by immortalized cell cultures from the renal proximal tubule of normal and Hyp mice also argued in favor of a humoral mediation (32,33). More recently, we demonstrated the direct intervention of a humoral factor, present in Hyp mice, on P i uptake inhibition by primary mouse proximal tubule cells in vitro, and we also showed that Hyp osteoblasts could produce and/or modify this factor (25).The PHEX/Phex (human/mouse) gene (phosphateregulating gene with homologies to endopeptidases on the X chromosome) has been shown to be mutated in XLH patients (16) and in Hyp mice (9). Because PHEX/ Phex codes for a putative neutral endopeptidase, it was suggested that the enzyme could either inactivate an inhibitor of phosphate reabsorption or hydrolyze a propeptide that stimulates phosph...

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Micropuncture study of renal phosphorus transport in hypophosphatemic vitamin D resistant rickets mice

Cited by 64 publications

References 38 publications

Renal Na(+)-phosphate cotransport in murine X-linked hypophosphatemic rickets. Molecular characterization.

Renal Na(+)-phosphate cotransport in murine X-linked hypophosphatemic rickets. Molecular characterization.

Mouse Mutants as Models in Endocrine Research

Role of abnormal neutral endopeptidase-like activities inHyp mouse bone cells in renal phosphate transport

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