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-Hydroxylase Gene Expression1
Department of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, Japan
Address all correspondence and requests for reprints to: Matsuhiko Hayashi, M.D., Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan. E-mail: matuhiko{at}mc.med.keio.ac.jp
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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,25-dihydroxyvitamin D3
[1,25-(OH)2D3] concentrations. To determine
the molecular mechanisms of this regulation, the effects of dietary
phosphorus deprivation and hypophysectomy on 25-hydroxyvitamin
D3 1-hydroxylase (1-hydroxylase) protein and
messenger RNA (mRNA) expression were examined in rats. A low phosphorus
diet (LPD) for 4 days resulted in hypophosphatemia and an increase in
serum 1,25-(OH)2D3 levels. This increase was
caused by the induction of 1-hydroxylase protein and mRNA expression
(4- and 10-fold increases, respectively). Administration of the
LPD or normal phosphorus diet to hypophysectomized (HPX) rats
resulted in hypophosphatemia and suppression of 1-hydroxylase
gene expression, indicating that hypophosphatemia itself is not
sufficient to induce 1-hydroxylase mRNA expression. Administration
of GH to HPX rats fed LPD could partially restore 1-hydroxylase mRNA
expression, whereas supplementation with insulin-like growth factor I,
T3, estrogen, or corticosterone had no effect. We also
examined Phex gene expression in the bone, because the clinical
features of X-linked hypophosphatemia resemble those of HPX rats. Phex
mRNA expression, however, was not altered in HPX rats. In conclusion,
we demonstrated that the increase in serum
1,25-(OH)2D3 levels caused by dietary
phosphorus deprivation is due to the induction of 1-hydroxylase mRNA
expression, and this increase is mediated in part by a GH-dependent
mechanism. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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,25-dihydroxyvitamin
D3
[1,25-(OH)2D3], is
synthesized by 25-hydroxyvitamin D3
1-hydroxylase (1-hydroxylase) from its endogenous precursor,
25-hydroxyvitamin D3 (1). This
enzyme is a member of the cytochrome P450 superfamily and is
predominantly localized in renal proximal tubular cells
(2). The serum level of
1,25-(OH)2D3 is primarily
controlled by this enzyme rather than by the other enzymes involved in
vitamin D3 metabolism.
The activity of 1-hydroxylase is closely regulated by a series of
modulators, including PTH, calcitonin, insulin-like growth factor I
(IGF-I), and 1,25-(OH)2D3
itself (3, 4, 5, 6, 7). Hypophosphatemia induced by dietary
phosphorus deprivation is also an important up-regulator of
1-hydroxylase activity in experimental animals (8, 9)
and in humans (10, 11). Previous studies have shown that
the increase in serum
1,25-(OH)2D3 levels in
response to a low phosphorus diet (LPD) is not dependent on PTH, but
can be completely blocked by hypophysectomy (9, 12). It
has been proposed that the pituitary GH-IGF-I axis is the mediator of
1,25-(OH)2D3 synthesis by
hypophosphatemia (13, 14, 15), although serum phosphate levels
are not associated with changes in GH secretion (12).
Recently, we and other investigators have cloned rat, mouse, human, and
porcine complementary DNAs (cDNAs) of 1-hydroxylase
(16, 17, 18, 19, 20, 21), facilitating studies of the mechanism by which
dietary phosphorus deprivation elevates serum
1,25-(OH)2D3 concentrations
at the molecular level. In the present study we examined the effects of
LPD and hypophysectomy on serum
1,25-(OH)2D3 levels,
1-hydroxylase protein expression, and 1-hydroxylase messenger
RNA (mRNA) expression in rats. Moreover, we tested whether the Phex
gene, mutations in which cause X-linked hypophosphatemia
(22), was involved in the regulation of 1-hydroxylase
by dietary phosphorus deprivation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To examine the effect of IGF-I on hypophysectomized (HPX) rats fed LPD, we used surgically implantable Alzet miniosmotic pumps (model 2001, Alza Corp., Palo Alto, CA). Rats were anesthetized, an Alzet pump filled with recombinant human IGF-I (Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan) dissolved in saline was inserted sc, and the incision was rapidly closed off. The animals received continuous infusion of IGF-I at 150 µg/day for 4 days. In an experiment designed to assess the effect of GH, T3, estrogen (E2), or corticosterone on (HPX) rats, hormone replacement experiments were performed. The doses used in this study were based on previous studies (13, 15, 23, 24). Human GH at a dose of 50 µg (Chemicon, Temecula, CA) was injected ip in four doses, given at 12-h intervals over the last 38-h period in HPX rats eating LPD for a total of 4 days. T3 (Sigma, St. Louis, MO) at 1 µg/day, E2 (Sigma) at 2 µg/day, or corticosterone (Sigma) at 100 µg/day was injected ip for 4 days at 24-h intervals. The rats were killed 2 h after the fourth dose.
For the characterization of 1-hydroxylase antibody,
thyroparathyroidectomized rats and rats fed a vitamin
D3-deficient diet (25) were used.
The animal protocol was reviewed and approved by the animal care and
use committee at Keio University.
Antibody
Rabbit polyclonal antibody was raised against a synthetic
peptide corresponding to the 14 C-terminal amino acids of rat
1-hydroxylase. A cysteine residue was attached to the
N-terminus of the peptide to introduce the SH residue for coupling. The
15-amino acid CLVPERSIHLQFVDR was synthesized by the f-moc method. The
synthetic peptide conjugated with keyhole limpet hemocyanin by the
sulfo-m-maleimidobenzoyl-N-hydrosuccinimide method
was used to immunize 2 New Zealand White rabbits with Freund’s
complete adjuvant (first injection) or incomplete adjuvant (from second
injection). After 5 injections, a sufficient increase in the antibody
titer was confirmed by enzyme-linked immunosorbent assay, and serum was
collected. Specific antibodies were prepared from the antiserum by
affinity column chromatography using the antigen peptide coupled
to 2-fluoro-1-methylpyridinium
toluene-4-sulfonate-activated Cellulofine (Seikagaku Corp., Tokyo, Japan).
Immunoblotting
Kidneys were homogenized with a Teflon pestle in 10 vol
0.25 mol/liter sucrose, 1 mmol/liter EDTA, and 5 mmol/liter Tris-HCl,
pH 7.4. All manipulations were performed at 4 C. The homogenate was
centrifuged at 450 x g for 10 min. The supernatant was
centrifuged at 5500 x g for 10 min. The mitochondrial
pellet was dissolved in 1 mmol/liter EDTA and 50 mmol/liter Tris-HCl,
pH 7.4. Thirty micrograms of mitochondrial protein were subjected to
SDS-PAGE, followed by immunoblotting. SDS-PAGE was performed as
described by Laemmli (26) on 7.5% gels. Proteins were
transferred onto a Hybond enhanced chemiluminescence nitrocellulose
filter (Amersham Pharmacia Biotech, Uppsala, Sweden), and
probed with anti-1-hydroxylase antibody. Bound antibodies were
visualized using an enhanced chemiluminescence Western blotting system
(Amersham Pharmacia Biotech). Signal intensities of the
bands were measured with NIH image software version 1.57 (NIMH,
Bethesda, MD).
Northern blot analysis
Total RNA was extracted by the acid guanidinium thiocyanate-
phenol-chloroform method (27). Polyadenylated
[poly(A)+] RNA was then prepared using a
MicroPoly (A) Pure mRNA Purification Kit (Ambion, Inc.,
Austin, TX). Four micrograms of poly(A)+ RNA were
denatured with glyoxal and dimethylsulfoxide, fractionated on a 1%
agarose gel, and transferred onto a Hybond N+
nylon membrane (Amersham Pharmacia Biotech). Hybridization
was carried out in PerfectHyb solution (TOYOBO Co., Ltd., Osaka, Japan)
at 66 C for 8 h with a 32P randomly labeled
rat 1-hydroxylase cDNA probe (17). A final high
stringency wash was performed at 66 C in 0.1 x SSC (standard
saline citrate) and 0.1% SDS, and the membrane was exposed to a BAS
Imaging Plate (Fuji Photo Film Co., Ltd., Tokyo, Japan).
The membrane was rehybridized with a ß-actin probe (CLONTECH Laboratories, Inc., Palo Alta, CA).
Measurement of serum levels of calcium, phosphate, and
1,25-(OH)2D3
Serum 1,25-(OH)2D3
levels were measured as described previously (28). Serum
calcium and phosphate levels were measured using an autoanalyzer. Serum
PTH levels were measured by enzyme-linked immunosorbent assay
(Amersham Pharmacia Biotech).
Preparation of complementary RNA (cRNA) competitor
molecules
To enable quantification of Phex gene expression by
competitive RT-PCR, internal heterologous cRNA competitor molecules for
both Phex and ß-actin were designed and constructed. Briefly, 
DNA
was amplified by PCR with Phex primers
(5'-ATTTAGGTGACACTATAGAATACAGAAATCAGTCAGTCGAAGGCGGTACGGTCATCATCT-
GACAC-3' and
5'-TTATCATGAACCTCACTGGTTCGGTTCTCATGCGCCATCCTGGGAAGACTCC-3';
the underlined sequence corresponds to SP6 promoter
sequence, and the italic sequence corresponds to DNA
sequence) or ß-actin primers
(5'-ATTTA-GGTGACACTATAGAATACTGGAGAAGAGCTATGAGCTGGTACGGTCATCATCTGACAC-3'
and
5'-TTATCATGAAACTTGCGCTCAGGAGGAGCAATGGCGTGAGTATTACGAAGGTG-3')
using a Competitive DNA Construction Kit (Takara Shuzo Co., Ltd.,
Shiga, Japan). The resultant PCR products were in vitro
transcribed into cRNA by SP6 RNA polymerase (Competitive RNA
Transcription Kit, Takara Shuzo Co., Ltd.). Mutant heterologous cRNA
competitor concentrations were measured by spectrophotometer.
Competitive RT-PCR
Expression of rat Phex mRNA was measured by two steps of
competitive RT-PCR. The first step of RT-PCR was performed to measure
ß-actin mRNA expression from total RNA at 200 ng, and the second step
of RT-PCR was performed to quantify Phex gene expression from an equal
amount of total RNA adjusted by ß-actin gene expression levels. First
strand cDNA was prepared by concurrent RT of increasing dilutions of
cRNA competitor and wild-type total RNA using random hexamer (GeneAmp
RNA PCR Core Kit, PE Applied Biosystems, Foster City, CA),
according to the manufacturer’s instructions. After an initial
denaturation for 3 min at 93 C, 30 cycles of PCR were performed for
ß-actin with ß-actin-sense (5'-TGGAGAAGAGCTATGAGCTG-3') and
ß-actin-antisense (5'-ACTTGCGCTCAGGAGGAGCAATG-3') primers, and 35
cycles for Phex with Phex-sense (5'-AGAAATCAGTCAGTCGAAGGCG-3') and
Phex-antisense (5'-CCTCACTGGTTCGGTTCTCATG-3') primers. Each cycle was
programmed as follows: 1-min denaturation at 93 C, 2-min annealing at
64 C, and 2-min extension at 72 C. The PCR products were separated by
3% agarose gel electrophoresis and stained by ethidium bromide. The
image was scanned and analyzed using NIH Image software. The expression
of wild-type mRNA was determined from the equivalence point
i.e. where the ratio of wild-type mRNA to cRNA competitor
equals 1.
Statistical analysis
Data are expressed as the mean ± SEM.
Student’s unpaired t test and one-way ANOVA with
Scheffé’s post-hoc test were used for statistical
comparisons between experimental groups. P < 0.05 was
considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-hydroxylase antibody-hydroxylase. This antibody was produced against a synthetic
peptide corresponding to the 14 C-terminal amino acids of rat
1-hydroxylase, which is unique for 1-hydroxylase. The specificity
of the antibody was tested by immunoblot analysis with homogenates
prepared from thyroparathyroidectomized rats and vitamin
D3-deficient rats. In the
thyroparathyroidectomized rat, the serum level of
1,25-(OH)2D3 is low,
providing a model of diminished 1-hydroxylase activity, whereas the
vitamin D3-deficient rat is a model of elevated
1-hydroxylase activity. The antibody recognized a major band at
approximately 55 kDa (Fig. 1A
) in a
homogenate of vitamin D3-deficient rat kidney.
The band was abolished by pretreatment of the antibody with the antigen
peptide (Fig. 1B). In contrast, only a nonspecific band was detected in
the thyroparathyroidectomized rat kidney. The size and the pattern of
regulation were consistent with previous studies (18, 25).
These results indicate this antibody recognizes the 1-hydroxylase
protein.
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-hydroxylase protein and mRNA
expression-hydroxylase protein and mRNA
expression in rats. LPD for 4 days significantly increased the serum
concentration of
1,25-(OH)2D3 (915 ±
68 pg/ml; vs. rats fed NPD, 288 ± 14 pg/ml;
P < 0.05; Table 1) and
also increased renal 1-hydroxylase protein (406 ± 18% of that
in rats fed NPD; P < 0.05; Fig. 2). These increases were accompanied by a
significant induction of 1-hydroxylase mRNA expression (1070 ±
206% of that in rats fed NPD; P < 0.05; Fig. 3), indicating that the LPD modulates
1-hydroxylase expression at the mRNA level.
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-hydroxylase mRNA
expression-hydroxylase activity by phosphorus
deprivation (9, 12). We examined the effect of
hypophysectomy on 1-hydroxylase mRNA expression. HPX rats receiving
LPD or NPD for 4 days developed hypophosphatemia (Table 2); however, neither treatment increased
serum 1,25-(OH)2D3 levels
(HPX rats fed LPD, 130 ± 45 pg/ml; HPX rats fed NPD, 292 ±
32 pg/ml) nor 1-hydroxylase gene expression (HPX rats fed LPD,
69 ± 17%; HPX rats fed NPD, 186 ± 61% of normal rats fed
NPD; Fig. 4). Conversely, serum
1,25-(OH)2D3 levels were
lower in HPX rats fed LPD than in HPX rats fed NPD
(P < 0.05). To examine the involvement of other
hormones in this paradoxical regulation, we measured serum PTH
concentrations in HPX rats fed LPD or NPD. However, serum PTH levels
were decreased and not different in the two groups (HPX rats fed LPD,
1.3 ± 0.3 pg/ml; HPX rats fed NPD, 1.6 ± 0.4 pg/ml). Other
factors may contribute to this phenomenon.
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-hydroxylase mRNA expression in HPX
rats-hydroxylase gene expression in HPX rats
(13, 14, 15, 29). We performed continuous infusion of IGF-I or
intermittent ip injection of GH (50 µg/dose, four times) in HPX rats
given LPD. Infusion of IGF-I at 150 µg/day for 4 days had no effect
on serum 1,25-(OH)2D3
levels (73 ± 22 pg/ml; Table 3),
nor did it restore 1-hydroxylase mRNA expression (87 ± 39% of
that in normal rats fed NPD; Fig. 5),
whereas the same dose of IGF-I increased serum
1,25-(OH)2D3 levels
(397 ± 33 pg/ml; vs. control rats, 288 ± 14
pg/ml; P < 0.05), 1-hydroxylase protein expression
(1.80 ± 34%; P < 0.05; Fig. 6A), and 1-hydroxylase gene expression
(306 ± 73%; P < 0.05; Fig. 6B) in normal
rats. In contrast, ip administration of GH partially restored
1-hydroxylase mRNA expression (187 ± 50% of that in normal
rats fed NPD; Fig. 5), but did not increase serum levels of
1,25-(OH)2D3 (123 ±
19 pg/ml).
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-hydroxylase mRNA expression in HPX rats-hydroxylase gene expression, HPX rats eating LPD were
replaced with T3, E2, or
corticosterone for 4 days. As shown in Fig. 7 and Table 3
, these hormones had no
effect on 1-hydroxylase gene expression or serum
1,25-(OH)2D3 levels in HPX
rats. Serum 1,25-(OH)2D3
levels in HPX rats fed LPD with T3 were
decreased.
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). Moreover, Phex mRNA
expression was not altered in any group examined, i.e.
normal rats fed LPD, normal rats fed NPD, HPX rats fed LPD, or HPX rats
fed NPD. Similar results were obtained for Phex gene expression in the
lung (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-hydroxylase protein expression, and 1-hydroxylase mRNA
expression in rats. Our study clearly demonstrated that the elevation
of serum 1,25-(OH)2D3
concentrations during LPD was caused by the induction of
1-hydroxylase gene expression in the kidney. We also showed that
hypophysectomy completely abolished the induction of 1-hydroxylase
gene by hypophosphatemia, and that it could be partially restored by
the pituitary hormone GH, but not by IGF-I, T3,
E2, or corticosterone. Moreover, Phex gene
expression was unaffected by either dietary phosphorus content or
hypophysectomy, indicating that it is not involved in 1-hydroxylase
gene induction by hypophosphatemia.
Serum 1,25-(OH)2D3 levels
are regulated by a number of factors, including PTH, calcitonin, IGF-I,
and serum concentrations of calcium and phosphate. Of these factors, it
has been reported that PTH (30, 31) and calcitonin
(25, 31, 32), respectively, induce 1-hydroxylase mRNA
expression and thereby increase serum
1,25-(OH)2D3
concentrations. In addition, we have shown here that restriction of
dietary phosphorus also induced 1-hydroxylase mRNA and protein
expression accompanied by an elevation in
1,25-(OH)2D3 levels. Two
mechanisms have been proposed for the regulation of serum
1,25-(OH)2D3 concentrations
by dietary phosphorus deprivation; one is the down-regulation of 25-
hydroxyvitamin D3 24-hydroxylase activity,
leading to the suppression of vitamin D3
catabolism, and the other is the phosphorylation/dephosphorylation of
ferredoxin, leading to posttranslational regulation of 1-hydroxylase
activity (33, 34). However, our study has demonstrated
that the major effect of dietary phosphorus restriction on
1,25-(OH)2D3 synthesis was
mediated by induction of the 1-hydroxylase gene.
Despite hypophosphatemia, 1-hydroxylase gene expression and serum
1,25-(OH)2D3 concentrations
were not increased in HPX rats, suggesting that hypophosphatemia itself
is not sufficient to increase 1-hydroxylase gene expression. This
suggests that hypophosphatemia is not directly sensed in the kidney and
may therefore be mediated by the pituitary. Consistent with our data,
several investigators have reported the absence of induction of
1-hydroxylase activity by hypophosphatemia in HPX rats (9, 12). Tenenhouse et al. (12) demonstrated
that dietary phosphorus deprivation increased both sodium-dependent
phosphate transport at the renal brush-border membrane and plasma
concentrations of
1,25-(OH)2D3, but only
enhanced phosphate transport was seen after hypophysectomy. Their data
indicated that the induction of renal phosphate transport and
1,25-(OH)2D3 synthesis by
hypophosphatemia were subject to different regulatory mechanisms. Thus,
the induction of 1-hydroxylase gene expression by hypophosphatemia
would be involved in the pituitary gland, whereas a low phosphate
stimulus directly increases sodium-dependent phosphate transport.
Although no specific phosphate sensor has been detected to date, it is
likely that the signal to synthesize
1,25-(OH)2D3 in the kidney
induced by low phosphate concentrations was transduced via the
pituitary gland.
Previous studies have indicated that GH and its mediator IGF-I could
restore the decreased 1-hydroxylase activity in HPX rats
(13, 14, 15, 29). It was therefore considered that the
pituitary GH-IGF-I axis was the mediator of hypophosphatemia-induced
1,25-(OH)2D3 synthesis.
However, several reports have suggested that the effects of dietary
phosphorus deprivation and IGF-I were independent of each other
(5, 12, 23). It was reported that hypophosphatemia was not
associated with changes in GH secretion (12) or plasma
IGF-I concentrations (23). Moreover, the responses to the
maximally effective dose of IGF-I and phosphate depletion on renal
1-hydroxylase activity were additive in rats (5). These
results suggested that IGF-I-dependent and hypophosphatemia-dependent
enzyme stimulation occurred via different mechanisms. Our findings that
GH, but not IGF-I, could partially restore the diminished
1-hydroxylase gene expression in HPX rats support the idea that
these stimuli were independent. Alternatively, the pituitary GH signal
by hypophosphatemia might be IGF-I independent and directly increase
1-hydroxylase gene expression in the kidney.
We looked for other factors that may be involved in induction of
1-hydroxylase gene expression by LPD, because GH alone could not
completely recover 1-hydroxylase gene expression in HPX rats. We
hypothesized that dysregulation of Phex gene expression might play a
role in hypophosphatemia and suppression of
1,25-(OH)2D3 levels in HPX
rats. Mutations in the Phex gene cause X-linked hypophosphatemia, which
is characterized by growth retardation, rachitic and osteomalacic bone
disease, hypophosphatemia, and renal defects in the reabsorption of
filtered phosphate and the metabolism of vitamin
D3 (22). However, no changes in Phex
mRNA expression were seen in this study. The Phex gene encodes for a
protein with homology to members of the membrane-bound zinc
metallopeptidase family (35). It is conceivable that the
gene product activates or inactivates an unidentified factor named
phosphatonin, and that activated phosphatonin regulates renal phosphate
transport and 1,25-(OH)2D3
synthesis. To date, phosphatonin and
1,25-(OH)2D3 are the only
known factors that suppress serum
1,25-(OH)2D3 levels. It is
possible that phosphatonin itself may be regulated and affect renal
1-hydroxylase gene induction in the hypophosphatemic state.
The available data indicate that regulation of phosphate homeostasis is
a complex, but fascinating, process. Identification of a phosphate
sensor and phosphatonin will clarify the mechanisms by which
hypophosphatemia during dietary phosphorus deprivation increases
1-hydroxylase gene expression in the kidney.
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Footnotes |
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Received September 11, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-hydroxylase and 24-hydroxylase
along the rat nephron. Proc Natl Acad Sci USA 78:1199–1203-hydroxylase in proximal straight tubule
of rat kidney. Nature 291:327–329[CrossRef][Medline]
,25-dihydroxyvitamin
D3 by calcium and phosphate in the rat. Science 190:578–580-hydroxylase cDNA. Proc
Natl Acad Sci USA 94:12920–12925-hydroxylase and vitamin D synthesis. Science 277:1827–1830-hydroxylase. Biochem Biophys Res Commun 239:527–533[CrossRef][Medline]
-hydroxylase and mutations causing vitamin D-dependent rickets
type 1. Mol Endocrinol 11:1961–1070-hydroxylase and its regulation by cAMP in
LLC-PK1 cells. J Am Soc Nephrol 10:963–970-hydroxylase gene in normocalcemic rats.
Proc Natl Acad Sci USA 96:8253–8258-hydroxylase gene
promoter. Proc Natl Acad Sci USA 95:1387–1391-hydroxylase gene
by parathyroid hormone, calcitonin, and 1, 25
(OH)2D3 in intact animals.
Endocrinology 140:2224–2231-hydroxylase mRNA expression via protein
kinase C pathway in LLC-PK1 cells. J Am Soc
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