Calbindin Vitamin D ~ Candice Bloom Vigor

Calbindin Vitamin D

Analysis of Vitamin D-Dependent Calcium-Binding Protein Messenger Ribonucleic Acid Expression in Mice Lacking the Vitamin D Receptor ^*

Yan Chun Li,

1Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114

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Alison E. Pirro,

1Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114

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Marie B. Demay

1Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114

*Address all correspondence and requests for reprints to: Marie B. Demay, M.D., Endocrine Unit, Wellman 501, Massachusetts General Hospital, 32 Fruit Street, Boston, Massachusetts 02114.

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This work was supported by NIH Grant DK-46974 (to M.B.D.).

Author Notes

Received:

10 September 1997

To investigate the roles of the receptor-dependent actions of 1,25-dihydroxyvitamin D₃[ 1,25-(OH)₂D₃] in the regulation of vitamin D-dependent calcium-binding proteins (calbindin-D), the messenger RNA (mRNA) levels of calbindin-D9k and -28k were examined in vitamin D receptor (VDR)-ablated mice and control littermates. In VDR-ablated mice, calbindin-D9k mRNA was dramatically reduced in the intestine, kidneys, lungs, and brain; however, calbindin-D28k mRNA was only moderately decreased in the kidney. After 1,25-(OH)₂D₃ injection, calbindin-D9k mRNA levels and renal and alveolar calbindin-D28k mRNA levels were induced in control animals, but not in the homozygous mice.

When the mice were fed a diet high in lactose, calcium, and phosphorus, intestinal calbindin-D9k mRNA levels in the homozygous mice were restored to those in their control littermates. However, this diet failed to normalize extraintestinal calbindin mRNA levels.

These findings demonstrate that the receptor-dependent actions of 1,25-(OH)₂D₃ regulate calbindin-D9k gene expression and that tissue-specific factors modulate the effects of 1,25-(OH)₂D₃ on calbindin-D28k gene expression. These data also demonstrate that in the absence of a functional VDR, a high local concentration of calcium, phosphorus, and/or lactose in the intestinal lumen can normalize intestinal calbindin-D9k mRNA levels.

VITAMIN D-dependent calcium-binding proteins (calbindin-D) are the major proteins thought to be involved in intracellular calcium transport in the intestine and the kidneys (1). Two classes of calbindin-D have been described in mammals: the 9,000-dalton calbindin (calbindin-D9k) and the 28,000-dalton calbindin (calbindin-D28k). Only calbindin-D28k is found in avian species (2). First identified in the intestine (3–5), calbindin-D9k is also expressed in the kidneys (6, 7), the placenta, the yolk sac (8–10), and the lungs (11). Calbindin-D28k is highly expressed in avian intestine (12, 13) and in avian and mammalian kidneys (6, 7, 14–16). It is also found in other tissues, including the brain (17–19), the pancreas (20–22), and chicken egg shell gland (23). The expression of calbindin-D9k and calbindin-D28k in the intestine and kidneys has been shown to be regulated by 1,25-dihydroxyvitamin D₃ [1,25-(OH)₂D₃] in animal models as well as in cell and organ cultures (24–30). A vitamin D response element has been identified in both the rat calbindin-D9k (31) and the mouse calbindin-D28k (32) gene promoters. Although attempts to find such an element in the chicken calbindin-D28k promoter have been unsuccessful (33, 34), experiments using 1,25-(OH)₂D₃ analogs in chicks demonstrate a correlation between 1,25-(OH)₂D₃ receptor binding and the induction of intestinal calbindin-D28k messenger RNA (mRNA) (35), suggesting that the genomic actions of 1,25-(OH)₂D₃ play a key role in the regulation of this gene. The regulation of calbindin-D9k and -28k by 1,25-(OH)₂D₃ has been thought to involve both transcriptional and posttranscriptional mechanisms (27, 36, 37). In other tissues, including the brain, the placenta, and the lungs, however, calbindin-D genes have not been shown to be regulated by 1,25-(OH)₂D₃ (11, 25, 38), suggesting that regulation of calbindin-D gene expression by 1,25-(OH)₂D₃ involves tissue-specific factors.

Calcium has also been found to modulate the actions of 1,25-(OH)₂D₃ on calbindin gene expression. In vitro experiments demonstrate that the induction of renal calbindin-D28k by 1,25-(OH)₂D₃ is enhanced by high levels of extracellular calcium (39). In rat duodenal organ cultures, calcium alone is able to stimulate calbindin-D9k mRNA synthesis (28). In chicks and rats, however, intestinal calbindin-D28k and -9k expression is induced by a low calcium diet and inhibited by a high calcium diet (40, 41). The molecular basis for the discrepancy between the in vitro and in vivo findings remains to be elucidated.

Although studies in vitamin D-deficient animals have contributed significantly to our understanding of calbindin-D gene expression, they have not distinguished the effects of hypocalcemia from those of vitamin D deficiency. To further clarify the relative contributions of the receptor-dependent actions of 1,25-(OH)₂D₃ and serum calcium to calbindin-D gene expression, we examined calbindin-D mRNA levels in the intestine, kidneys, brain, and lungs of mice with targeted ablation of the vitamin D receptor (VDR) on a normal diet as well as on a high lactose, high calcium, high phosphorus diet. The later dietary treatment normalized random blood ionized calcium in the VDR-ablated mice.

Materials and Methods

Animal maintenance

VDR null mice (42) and control mice were maintained in a virus- and parasite-free barrier facility and exposed to a 12-h light, 12-h dark cycle. The animals were fed autoclaved Purina rodent chow (5010, Ralston Purina, St. Louis, MO) containing 1% calcium, 0.67% phosphorus, 0% lactose, and 4.4 IU vitamin D/g. The γ-irradiated test diet (TD96348, Teklad, Madison, WI), containing 2% calcium, 1.25% phosphorus, and 20% lactose supplemented with 2.2 IU vitamin D/g, was begun at 19 days of age. For vitamin D treatment, 15 h before death, the animals were injected ip with 10 pmol 1,25-(OH)₂D₃ in propylene glycol. Serum ionized calcium determinations were performed using a Ciba/Corning Ca²⁺/pH analyzer.

RNA isolation

Mice were exsanguinated under anesthesia, and the brain, kidneys, duodenum, and lungs were removed immediately and placed into Trizol solution (Life Technologies, Bethesda, MD). The tissues were homogenized immediately using a Polytron (Brinkmann Instruments, Westbury, NY). Total RNA was isolated according to the Trizol manufacturer's instructions. RNA samples isolated from wild-type or heterozygous littermates were used as controls.

Northern blot analysis

Total RNA (25 μg) was denatured and separated in a 1.2% agarose gel containing 0.6 m formaldehyde as previously described (43). The RNA was transferred onto a Nylon 66 plus membrane (Pharmacia Biotech, San Francisco, CA) in 20 × SSC (standard saline citrate). The membrane was baked at 80 C for 2 h and hybridized with a complementary DNA (cDNA) probe labeled with[α -³²P]deoxy-ATP (New England Nuclear, Boston, MA) using a Random Primed Labeling kit (Boehringer Mannheim, Indianapolis, IN) or with a γ-³²P-labeled antisense oligonucleotide probe for 18S ribosomal RNA. The cDNA probes used were a 340-bp BamHI-PvuII fragment and a 1.2-kilobase BamHI-PvuII fragment of mouse calbindin-D9k and -28k cDNA, respectively (gifts from Dr. Sylvia Christakos, University of Medicine and Dentistry of New Jersey, Newark, NJ). Hybridization was carried out at 42 C in a solution containing 50% formamide, 6 × SSPE (1 × SPPE = 180 mm NaCl, 10 mm NaH₂PO₄, 1 mm EDTA, pH 7.4), 5× Denhardt's solution, 0.5% SDS, and 100 μg/ml denatured salmon sperm DNA. After hybridization, the membranes were exposed to x-ray films (Eastman Kodak, Rochester, NY) at −80 C for autoradiography. The relative amount of mRNA was assessed by densitometric scanning of autoradiograms. β-Actin and 18S ribosomal RNA signals were used to normalize for variations in RNA loading.

Results

The expression of calbindin-D9k and -28k mRNAs was examined in control and VDR-ablated mouse littermates. As shown in Fig. 1A, in the duodenum, calbindin-D9k mRNA levels were markedly reduced in the homozygous mice at 2, 5, and 11 weeks of age (6.4 ± 1.6-fold reduction by 11 weeks). The mRNA levels of the heterozygotes were identical to those of the wild-type littermates (data not shown), consistent with their normal phenotype (42). As reported previously (24, 25), calbindin-D28k mRNA was undetectable in the intestine of mice from all three groups. The expression of calbindin-D9k and 28k mRNAs in the kidney was also examined (Fig. 1B). Although calbindin-D9k mRNA was barely detectable in homozygous mice at 2, 5, and 11 weeks of age, the level of calbindin-D28k mRNA was only moderately reduced (1.32 ± 0.02-fold reduction by 11 weeks, based on the smallest mRNA species). Consistent with previous reports, three calbindin-D28k mRNA species were present in the kidney (25, 37). Both calbindin-D9k and -28k mRNA levels of the heterozygous mice were identical to those of their wild-type littermates (not shown). In the brain, calbindin-D9k mRNA expression was detected in the wild-type and heterozygous mice and was drastically reduced in the homozygous littermates (Fig. 1C). However, brain calbindin-D28k mRNA levels in the homozygotes were identical to those of the wild-type and heterozygous littermates (Fig. 1C). In the lungs, calbindin-D9k mRNA was reduced in the homozygous mice (2.1± 0.3-fold reduction), whereas calbindin-D28k mRNA levels were not affected (Fig. 1D).

Figure 1.

Calbindin-D mRNA expression in VDR knock-out mice. Total RNA was isolated from mouse littermates of different age groups as indicated. Twenty-five micrograms of total RNA per lane were used for Northern blot analysis. The membrane was sequentially hybridized with mouse calbindin-D9k, calbindin-D28k, and β-actin cDNA probes.β -Actin mRNA serves as an internal control for RNA loading. +/+, Wild type; +/−, heterozygote; −/−, homozygote; CaBP-D, calbindin-D. A, Calbindin-D mRNA expression in the intestine. Total RNA was isolated from the duodenum of 2-, 5-, and 11-week-old littermates and subjected to Northern analysis. B, Calbindin-D mRNA expression in the kidney. Total RNA, used for Northern analysis, was isolated from the kidneys of 2-, 5-, and 11-week-old littermates as indicated. C, Calbindin-D mRNA expression in the brain. Total RNA was isolated from the whole brain of 5-week-old littermates. D, Calbindin-D mRNA expression in the lung. Total RNA was isolated from lungs of the 11-week-old littermates.

Figure 1.

To further evaluate the effects of receptor-dependent actions of 1,25-(OH)₂D₃ on calbindin-D gene expression, 1,25-(OH)₂D₃ was injected into VDR-ablated and heterozygous littermates at 11 weeks of age, and RNA was isolated from the intestine, kidneys, brain, and lungs 15 h later. This time point was chosen because previous reports showed that both calbindin-D9k and -28k mRNAs were induced in this time frame in vitamin D-deficient animals (24, 25). As shown in Fig. 2, in the heterozygous mice, calbindin-D9k mRNA levels were induced 2.1 ± 0.14-fold in the intestine (Fig. 2A), 1.8 ± 0.02-fold in the kidneys (Fig. 2B), and 1.7 ± 0.06-fold in the lungs (Fig. 2D) in response to 1,25-(OH)₂D₃, but calbindin-D9k levels were not changed by 1,25-(OH)₂D₃ treatment in the homozygous receptor-ablated mice (Fig. 2). Calbindin-D28k mRNA expression was also induced by 1,25-(OH)₂D₃ in the kidneys (1.3 ± 0.16-fold induction; Fig. 2B) and lungs (1.79 ± 0.31-fold induction; Fig. 2D) of the heterozygous mice, but not in those of the homozygous mice. In the brain, calbindin-D28k mRNA was unchanged by 1,25-(OH)₂D₃ treatment (Fig. 2C).

Figure 2.

Induction of calbindin-D mRNA by 1,25-(OH)₂D₃. Mouse littermates (9 weeks old) were injected ip with 10 pmol 1,25-(OH)₂D₃/mouse and killed 15 h later for RNA isolation. Twenty-five micrograms of total RNA isolated from the intestine (A), kidneys (B), brain (C), and lungs (D) were used for Northern blot analysis. The membrane was sequentially hybridized with calbindin-D9k, calbindin-D28k, and β-actin cDNA probes. +/−, Heterozygote; −/−, homozygote; CaBP-D, calbindin-D; +D, mouse injected with 1,25-(OH)₂D₃ as described in Materials and Methods.

Figure 2.

To examine the effects of calcium and phosphorus on calbindin-D gene expression in the absence of the genomic actions of 1,25-(OH)₂D₃, the mice were fed a diet high in lactose, calcium, and phosphorus. As shown in Fig. 3, this diet normalized intestinal calbindin-D9k mRNA expression in 5-week-old VDR-ablated mice (Fig. 3A). Similar results were obtained in 11-week-old littermates (data not shown). However, renal (Fig. 3B) and brain (not shown) calbindin-D9k mRNA levels in the homozygous mice failed to normalize, as did renal calbindin-D28k mRNA levels (Fig. 3B).

Figure 3.

Effects of dietary calcium, phosphorus, and/or lactose on calbindin-D mRNA expression. Mice were fed the TD96348 diet as described in Materials and Methods. Total RNA was isolated from the duodenum and kidneys of 5-week-old littermates. Twenty-five micrograms of total RNA were used in each lane. The membrane was hybridized sequentially with calbindin-D9k, calbindin-D28k, and β-actin cDNA probes or an antisense oligonucleotide probe of 18S ribosomal RNA. +/+, Wildtype; −/−, homozygote; CaBP-D, calbindin-D. A, Calbindin-D9k mRNA expression in the intestine. B, Calbindin-D9k and 28k mRNA expression in the kidney.

Figure 3.

Discussion

In vivo studies of the receptor-dependent actions of 1,25-(OH)₂D₃ on calbindin-D gene expression have been complicated by the inability to differentiate the effects of hormone deficiency from those of hypocalcemia. The model we have used, an in vivo model of VDR deficiency, allows a more precise evaluation of the genomic effects of 1,25-(OH)₂D₃ on target gene expression. The effects of VDR ablation on calbindin-D9k and 28k mRNA levels are summarized in Table 1.

Table 1.

Expression of calbindin-D9k and 28k mRNA

	Calbindin-D9k				Calbindin-D28k				Ca²⁺ (mmol/liter) ^a
	Intestine	Kidney	Brain	Lung	Intestine	Kidney	Brain	Lung	Ca²⁺ (mmol/liter) ^a
KO/regular diet	↓	↓	↓	↓	ND	↓	N	N	1.0 ± 0.04 ^b
KO/rescue diet	N	↓	↓	NE	ND	↓	N	NE	1.37 ± 0.03 ^c
KO/+D	↓	↓	↓	↓	ND	↓	N	N	NE
C/+D	↑	↑	↑	↑	ND	↑	N	↑	NE

	Calbindin-D9k				Calbindin-D28k				Ca²⁺ (mmol/liter) ^a
	Intestine	Kidney	Brain	Lung	Intestine	Kidney	Brain	Lung	Ca²⁺ (mmol/liter) ^a
KO/regular diet	↓	↓	↓	↓	ND	↓	N	N	1.0 ± 0.04 ^b
KO/rescue diet	N	↓	↓	NE	ND	↓	N	NE	1.37 ± 0.03 ^c
KO/+D	↓	↓	↓	↓	ND	↓	N	N	NE
C/+D	↑	↑	↑	↑	ND	↑	N	↑	NE

KO, VDR knock-out mice; C, control mice; N, normal; NE, not examined; ND, not detectable; +D, 1,25-(OH)₂D₃ treatment; ↑, increased; ↓, decreased.

Mean ionized calcium at 11 weeks.

Control littermates, 1.31 ± 0.01.

Control littermates, 1.36 ± 0.03.

Table 1.

Expression of calbindin-D9k and 28k mRNA

	Calbindin-D9k				Calbindin-D28k				Ca²⁺ (mmol/liter) ^a
	Intestine	Kidney	Brain	Lung	Intestine	Kidney	Brain	Lung	Ca²⁺ (mmol/liter) ^a
KO/regular diet	↓	↓	↓	↓	ND	↓	N	N	1.0 ± 0.04 ^b
KO/rescue diet	N	↓	↓	NE	ND	↓	N	NE	1.37 ± 0.03 ^c
KO/+D	↓	↓	↓	↓	ND	↓	N	N	NE
C/+D	↑	↑	↑	↑	ND	↑	N	↑	NE

	Calbindin-D9k				Calbindin-D28k				Ca²⁺ (mmol/liter) ^a
	Intestine	Kidney	Brain	Lung	Intestine	Kidney	Brain	Lung	Ca²⁺ (mmol/liter) ^a
KO/regular diet	↓	↓	↓	↓	ND	↓	N	N	1.0 ± 0.04 ^b
KO/rescue diet	N	↓	↓	NE	ND	↓	N	NE	1.37 ± 0.03 ^c
KO/+D	↓	↓	↓	↓	ND	↓	N	N	NE
C/+D	↑	↑	↑	↑	ND	↑	N	↑	NE

KO, VDR knock-out mice; C, control mice; N, normal; NE, not examined; ND, not detectable; +D, 1,25-(OH)₂D₃ treatment; ↑, increased; ↓, decreased.

Mean ionized calcium at 11 weeks.

Control littermates, 1.31 ± 0.01.

Control littermates, 1.36 ± 0.03.

Consistent with observations in vitamin D-deficient animals, calbindin-D9k mRNA levels were dramatically reduced in the kidney and intestine of the receptor-ablated mice. It is of interest, however, that unlike observations in murine models of vitamin D deficiency (11), calbindin-D9k levels were reduced in the lungs and the brain as well. Treatment of control littermates with 1,25-(OH)₂D₃ induced calbindin-D9k mRNA in all tissues examined, confirming that calbindin-D9k gene expression is regulated by 1,25-(OH)₂D₃ in these tissues. A reduction of calbindin-D9k expression in the intestine and kidney was observed in normocalce-mic 2-week-old VDR-ablated mice (42), suggesting that it was a consequence of receptor deficiency rather than hypocalcemia.

Although vitamin D response elements have been found in both the murine calbindin-D9k and -28k genes (31, 32), our studies demonstrate that the VDR dependence of calbindin-D28k gene expression varies among the tissues examined. Consistent with the observation that the kidney and lungs express the VDR, calbindin-D28k mRNA levels in these tissues were induced in the control mice treated with 1,25-(OH)₂D₃. However, renal calbindin-D28k mRNA levels were moderately reduced, and alveolar calbindin-D28k expression was not affected by ablation of the VDR. These findings confirm the previous observation that a portion of renal calbindin-D28k expression is constitutive (44). The expression of calbindin-D28k in the lungs is a novel finding, and our data suggest that its basal expression is constitutive, although mRNA levels are induced by 1,25-(OH)₂D₃ treatment. In the brain, however, calbindin-D28K mRNA expression is largely restricted to the Purkinjie cells of the cerebellum, which do not express the VDR (2). Consistent with this observation, calbindin-D28K levels were not affected by VDR status, nor were they modulated by 1,25-(OH)₂D₃ treatment in control littermates.

The observation that a high lactose, high calcium, high phosphorus diet is able to normalize intestinal calbindin-D9k expression in the VDR-ablated mice supports the hypothesis that multiple factors interact to regulate expression of this gene in the enterocyte. The calcium, lactose, and phosphorus concentrations of this test diet are higher than those in regular lab chow and murine milk (45), suggesting that the high local concentration of one or more of these components is responsible for normalizing intestinal calbindin-D9K mRNA levels in the VDR-ablated mice by inducing either gene expression or mRNA stability. Although normalization of intestinal calbindin 9K mRNA levels results in normal random ionized calcium levels in VDR-ablated mice, studies of intestinal calcium absorption will be required to confirm that the defect in intestinal calcium transport in VDR-ablated mice is corrected along with the calbindin-D9k mRNA levels.

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Author notes

This work was supported by NIH Grant DK-46974 (to M.B.D.).

Calbindin Vitamin D

Source: https://academic.oup.com/endo/article/139/3/847/2987005

Candice Bloom Vigor