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Endocrinology Vol. 138, No. 6 2596-2600
Copyright © 1997 by The Endocrine Society

ARTICLES

In Vivo Regulation of Chromogranin A Messenger Ribonucleic Acid in the Parathyroid by 1,25-Dihydroxyvitamin D: Studies in Normal Rats and in Chronic Renal Insufficiency1

Eric Soliman, Lucie Canaff, John Fox and Geoffrey N. Hendy

Departments of Medicine and Physiology (E.S., L.C., G.N.H.), McGill University and Royal Victoria Hospital, Montreal, Quebec H3A 1A1, Canada; and NPS Pharmaceuticals (J.F.), Salt Lake City, Utah 84108

Address all correspondence and requests for reprints to: Geoffrey N. Hendy, Ph.D., Calcium Research Laboratory, Room H4.67, Royal Victoria Hospital, 687 Pine Avenue West, Montreal, Quebec H3A 1A1, Canada. E-mail: gnhendy{at}medcor.mcgill.ca


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Chromogranin-A (CgA) and PTH are the two major secretory products of the parathyroid gland. In vitro, 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] increases CgA, but decreases PTH messenger RNA (mRNA) levels. We investigated the physiological significance of the induced changes in CgA expression by examining the effects of 1,25-(OH)2D3 on parathyroid CgA mRNA levels in vivo. Normal rats were injected with 1,25-(OH)2D3 at 48 and 24 h before blood sampling and isolation of both parathyroid glands. Parathyroid total RNA was extracted and CgA and PTH mRNA quantified by Northern blot analysis. CgA mRNA levels increased 1.6-, 3.2- and 5.6-fold, whereas PTH mRNA levels decreased by 37, 63 and 97%, respectively, with 1,25-(OH)2D3 doses of 10, 50, and 250 pmol/100 g BW. Parathyroid gland CgA expression also was examined in rats with mild chronic renal insufficiency, induced by a 5/6 nephrectomy 5 weeks earlier. Chronic renal insufficiency rats, fed normal chow, had elevated serum urea, creatinine, and PTH levels and reduced 1,25-(OH)2D3 but normal serum levels of calcium and phosphate. PTH mRNA levels were elevated 4-fold and CgA mRNA levels were 50% lower in the uremic animals. This indicates that the regulation of CgA expression in normocalcemic rats occurs at physiological 1,25-(OH)2D3 concentrations. In summary, increases and decreases in serum 1,25-(OH)2D3 levels are associated with corresponding increases and decreases in CgA mRNA levels in the parathyroid glands of rats. Therefore, this study is the first to demonstrate the physiological relevance of the earlier in vitro observations.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
CHROMOGRANIN-A (CgA) and PTH are the two major secretory products of the parathyroid gland (1, 2). CgA, the principal member of the granin family of acidic glycoproteins, was originally identified in chromaffin granules of the adrenal medulla and is present in virtually all endocrine and neuroendocrine tissues (3). Because the granins are found costored and are cosecreted with the resident hormone or neurotransmitter, they are believed to be important for cell secretory activity. However, the precise function(s) of CgA, as well as other members of the granin family, such as chromogranin B (CgB), remains to be fully elucidated (3). One hypothesis suggests that CgA may act to target or chaperone peptide hormones to granules of the regulated secretory pathway. An alternate hypothesis suggests that CgA is cleaved intra- and/or extracellularly to release biologically active peptides that interact with the secretory cell in an autocrine or paracrine fashion to inhibit further hormone release. Indeed CgA, and several peptides thought to be derived from it, have been shown to inhibit PTH secretion in vitro (reviewed in 4).

Extracellular ionized calcium (Ca2+) and 1,25-dihydroxyvitamin D3 \[1,25-(OH)2D3\] are the main regulators of parathyroid gland synthetic and secretory activity (5, 6, 7, 8, 9, 10). In vitro studies, using bovine parathyroid cells in primary culture, have shown that the transcription and secretion rates of PTH and CgA are regulated in opposite directions by 1,25-(OH)2D3 (11, 12, 13, 14, 15). The sterol decreases PTH (8, 9, 10) but increases CgA gene expression in a time- and concentration-dependent fashion (13, 14). The regulation of PTH expression by Ca2+ and 1,25-(OH)2D3 has been confirmed in vivo (10, 16, 17). However, no study to date has investigated the regulation of parathyroid CgA gene expression in vivo.

In the hyperparathyroidism that is secondary to chronic renal insufficiency (CRI), increased PTH gene expression and PTH secretion are believed to be attributable, at least in part, to the reduced circulating levels of 1,25-(OH)2D3 (18, 19, 20, 21, 22, 23). Although several studies have focused on the elevated synthesis and secretion of PTH in CRI, none have examined the expression of parathyroid CgA. Therefore, to gain a better understanding of the physiological relevance of the regulation by 1,25-(OH)2D3 of CgA gene expression previously observed in vitro, we determined the effects on parathyroid CgA messenger RNA (mRNA) levels of increased and decreased 1,25-(OH)2D3 levels in normal and CRI rats. The results indicate that relatively small changes in circulating 1,25-(OH)2D3 can affect parathyroid CgA mRNA levels.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals, diets, and experimental procedures
Normal male Sprague-Dawley rats (Charles River, St. Constant, Quebec, Canada), weighing 180–200 g when received, were fed a standard rodent chow (Ralston-Purina, LaSalle, Quebec, Canada) containing 1.01% calcium, 0.74% phosphorus, and 3.3 IU vitamin D3/g. All animal experiments were carried out according to institutional guidelines.

For the studies that investigated the CgA mRNA response to 1,25-(OH)2D3, rats fed the above diet were divided into five groups. Each group was injected ip at 48 and 24 h before death. Group 1 was injected with vehicle (propylene glycol, 0.2 ml/100 g BW), whereas groups 2–4 received two injections of 1,25-(OH)2D3 at doses of 10, 50, or 250 pmol/100 g BW. Group 5 received 25-hydroxyvitamin D3 \[25(OH)D3\] at doses of 250 pmol/100 g BW.

Uremia was induced in the rats in the CRI studies by a one-stage, 5/6 nephrectomy procedure under pentobarbital anesthesia (60 mg/kg, ip). Control animals underwent a sham operation, which involved exposure of the kidneys and subsequent closure of the two separate flank incisions. The sham-operated and 5/6-nephrectomized rats were maintained on the standard chow. Five weeks after surgery, the rats were anesthetized with pentobarbital, a blood sample was collected by cardiac puncture, and the parathyroid and thyroid glands were microdissected separately.

Plasma analyses
Serum total calcium, phosphate, creatinine, and urea nitrogen levels were measured using Autoanalyzer techniques. Serum PTH levels were assessed using a sensitive two-site immunoradiometric assay kit for rat PTH-(1–34), which detects the intact PTH molecule and amino-terminal fragments equally (Immutopics, San Clemente, CA) (24). Serum PTH levels are reported as pg-equivalents of rat PTH-(1–34)/ml. Serum 1,25-(OH)2D3 levels were measured using a commercial RRA kit (Nichols, San Juan Capistrano, CA) (25).

RNA extraction
Parathyroid total RNA was obtained by the following method: Two microdissected glands from an individual animal were homogenized using a 22-gauge needle and 3-ml syringe in 300 µl 5 M guanidine isothiocyanate, 10 mM EDTA, 50 mM Tris, pH 7.5, containing 0.8% (vol/vol) 2-mercaptoethanol. Five volumes of 4 M LiCl was added, and the mixture was left overnight at 4 C. The solution was centrifuged at 10,000 x g, 30 min, 4 C; and the pellet was resuspended in 300 µl 50 mM Tris, pH 7.5, 5 mM EDTA, 0.5% SDS, 150 µg/µl proteinase K. Digestion was carried out at 37 C for 1 h. Further purification was performed by extraction with phenol-chloroform-isoamyl alcohol (50:50:1). To the recovered aqueous phase, 1/10 vol of 3 M sodium acetate (pH 5.2) was added. The RNA was precipitated overnight with ethanol at -20 C. The pellet, obtained by centrifugation, was lyophilized and resuspended in 10 µl diethylpyrocarbonate-treated H2O. Thyroid total RNA was obtained using the same method. Total RNA was isolated from rat pheochromocytoma PC-12 cells, as previously described (14), and used as a control for CgB mRNA expression.

Northern blot analysis
The entire vol (10 µl) of RNA was fractionated on a 1% agarose-0.66 M formaldehyde gel, transferred to Nytran by blotting, and fixed by baking the filter at 80 C for 2 h under vacuum.

Prehybridization and hybridization of Northern blots were performed in 1% BSA, 7% SDS, 0.5 M NaPO4 (pH 6.8), 1 mM EDTA. The probes were as follows: 1) CgA, a synthetic (36-mer) oligonucleotide (5'-AGTGTCCCCTTTTGTCATAGGGCTGTTCACAGGAAG-3') complementary to the rat CgA mRNA sequence encoding amino acids +1 to +12 (26); 2) CgB, a synthetic (39-mer) oligonucleotide (5'-AGTCACCATTTCTTCATTGTGGTCCCTGTTATCCACTGG-3') complementary to CgB mRNA sequence encoding amino acids +2 to +14 (27); 3) thyroglobulin (Tg), a synthetic (30-mer) oligonucleotide (5'-CAACAAAGTCGAGACCCACAAGACCAAGGT-3') complementary to the rat Tg mRNA sequence encoding amino acids +3 to +12 (28); 4) 28S ribosomal RNA (rRNA), a synthetic (30-mer) oligonucleotide (5'-CGTCGCTATGAACGCTTGGCCGCCACAAGC-3') complementary to nucleotides 4131–4160 at the 3' end of rat 28S rRNA (29); and 5) PTH, a 400-bp PstI-XbaI restriction fragment containing most of intron B and exon II of the rat PTH gene (30), subcloned into pGEM3 and kindly provided by Dr. Gerhard Heinrich. Oligonucleotides were 5'-end-labeled using [32P]ATP and T4 polynucleotide kinase, and the cDNA insert was labeled with [32P]deoxy-CTP by the random primer method to a specific activity of 109 cpm/µg \[31\].

Membranes were washed four times at 65 C in 0.5% BSA, 5% SDS, 1 mM EDTA, 40 mM NaPO4 (pH 6.8), and then four times at 65 C in 1% SDS, 1 mM EDTA, 40 mM NaPO4 (pH 6.8). They were subsequently exposed to Kodak XAR film (Eastman Kodak, Rochester, NY). Relative intensities were assessed using a LKB Ultroscan XL densitometer (LKB, Baie d’Urfe, Quebec, Canada). The signals for CgA and PTH mRNA were expressed relative to that for 28S rRNA.

Statistical analysis
Data are reported as mean ± SEM. The results from the 1,25-(OH)2D3 response studies were initially subjected to ANOVA. The significance of differences from control, vehicle-injected rats was then determined using Dunnett’s multiple comparison test. The significance of differences in the CRI studies was determined using Student’s t test. A P value less than 0.05 was taken to indicate a significant difference in both studies.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Successful microdissection of parathyroid gland free of thyroid tissue
As shown in Fig. 1Go, parathyroid gland RNA was virtually negative for Tg mRNA. Thus, the parathyroid glands were obtained essentially free of contaminating thyroid tissue. This was confirmed by histological analysis. Glands were randomly isolated, sectioned (1-µm thickness) and stained with methylene blue. Examination under light microscopy showed parathyroid glands surrounded by small amounts of loose connective tissue but very little, if any, thyroid tissue (data not shown). Isolation of parathyroid RNA free of thyroidal RNA is important because thyroid C cells express CgA mRNA.



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  		Figure 1. Successful microdissection of parathyroid gland, free of thyroid tissue. Tg mRNA (panel A), PTH mRNA (panel B), and 28S rRNA (panel C) were measured in rat parathyroid (P) and thyroid (T) glands by Northern blot analysis. In panel A, horizontal lines represent positions of 28S and 18S rRNA. Very low levels of Tg mRNA are present in lane P, panel A, indicating virtually no thyroid contamination of the microdissected parathyroid glands.

 
CgA, but not CgB, is expressed in the parathyroid gland
Several neuroendocrine tissues express both CgA and CgB. Therefore, we tested for both CgA and CgB mRNAs in the rat parathyroid gland. Whereas the parathyroid expressed a high level of CgA mRNA, it was negative for CgB (Fig. 2Go). In contrast, a high level of CgB mRNA was demonstrated in rat pheochromocytoma cells (Fig. 2Go).



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  		Figure 2. CgA, but not CgB, is expressed in the parathyroid. A, Rat parathyroid gland and rat pheochromocytoma PC12 cells demonstrated highly abundant expression of CgA; B, CgB was expressed only in PC12 cells; C, relative RNA quantity and quality were monitored by ethidium bromide staining of 28S and 18S rRNA.

 
1,25-(OH)2D3 increases parathyroid CgA mRNA levels in a dose-dependent manner
Serum Ca levels were increased significantly by the 50- and 250-, but not the 10-pmol/100 g doses of 1,25-(OH)2D3, whereas phosphate levels were increased significantly only by the highest dose (Table 1Go). In contrast, PTH levels were decreased significantly with all doses of 1,25-(OH)2D3. Serum 1,25-(OH)2D3 levels remained significantly elevated at 24 h after the second injection in the rats that received the 50- and 250-pmol/100 g doses of 1,25-(OH)2D3.


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  		Table 1. Serum biochemistries of vehicle- and 1,25(OH)2D3-injected rats

 
1,25-(OH)2D3 administration increased CgA mRNA levels in the parathyroid glands of normal rats in a dose-dependent manner (Fig. 3Go). When compared with vehicle-injected controls, CgA mRNA levels were, respectively, 1.6-, 3.2- and 5.6-fold higher in rats after the 10-, 50-, and 250-pmol/100 g doses of 1,25-(OH)2D3. Likewise, the regulation of PTH gene expression by 1,25-(OH)2D3 also was dose-dependent but in the opposite direction. Reductions in PTH mRNA levels of 37, 63, and 97%, respectively, were observed after the 10-, 50-, and 250-pmol/100 g doses. In contrast, neither CgA nor PTH mRNA levels were altered in the parathyroid glands of normal rats that received two 250-pmol/100 g injections of 25(OH)D3 (data not shown).



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  		Figure 3. 1,25-(OH)2D3 increases parathyroid CgA mRNA levels in a dose-dependent manner. Northern blot analysis was conducted on parathyroid RNA from rats injected with either vehicle or 10, 50, or 250 pmol 1,25-(OH)2D3/100 g at 48 and 24 h before death. CgA and PTH mRNA levels are expressed relative to 28S rRNA. Values are mean ± SE (n = 5–8). *, P < 0.05; **, P < 0.01: significance of difference from vehicle-injected controls. Whereas PTH mRNA levels are suppressed, those of parathyroid CgA mRNA are increased by 1,25-(OH)2D3.

 
CgA mRNA levels are decreased in parathyroid glands of normocalcemic uremic rats
Five weeks after 5/6 nephrectomy, the rats that were fed normal chow had significantly elevated serum levels of creatinine, urea nitrogen, and PTH when compared with sham-operated controls. However, Ca and phosphate concentrations remained normal despite a significantly lower serum 1,25-(OH)2D3 (Table 2Go). CgA mRNA levels were 50% lower than those in sham-operated animals, whereas PTH mRNA levels were elevated 4.0-fold (Fig. 4Go).


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  		Table 2. Serum biochemistries of sham-operated and 5/6-nephrectomized rats fed normal chow for 5 weeks after surgery

 


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  		Figure 4. Parathyroid CgA mRNA levels are decreased in normocalcemic uremic rats fed normal chow. A, Autoradiographs of representative Northern blots of parathyroid RNA from rats either sham-operated (SHAM) or 5/6-nephrectomized (5/6 Nx); B, CgA and PTH mRNA levels were assessed by densitometry and related to 28S rRNA. Each point is the mean ± SE (n = 5–8). Asterisks indicate a significant difference from sham (*, P < 0.05; **, P < 0.01). Whereas PTH mRNA levels are increased, those of parathyroid CgA mRNA are decreased in the 5/6 Nx rats.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In the present study, we show for the first time in vivo that parathyroid CgA gene expression is regulated in a dose-dependent manner by 1,25-(OH)2D3. Increases in serum 1,25-(OH)2D3 levels, after the administration of 1,25-(OH)2D3, that are associated with either no change or an increase in serum Ca2+, resulted in increased parathyroid CgA mRNA levels. Moreover, decreased 1,25-(OH)2D3 levels in normocalcemic rats with CRI resulted in decreased CgA mRNA levels. Finally, these studies confirmed the results of others that PTH mRNA levels decrease in a dose-dependent fashion in normal rats injected with 1,25-(OH)2D3 and are elevated in rats with CRI (10, 16, 21, 22, 32).

Expression of neither CgA nor CgB has been examined previously in the rat parathyroid gland. We detected abundant CgA mRNA expression by Northern blot analysis; however, a signal for CgB mRNA was not detected, suggesting that rat parathyroid gland expresses little, if any, CgB. CgA expression in human parathyroid glands has been demonstrated by Northern blot analysis, immunoblotting, immunohistochemistry, and RIA (33, 34, 35, 36, 37, 38, 39, 40). However, investigations of expression of the related granin family member, CgB, in normal human and adenomatous parathyroid tissue have been inconsistent, with most studies reporting negative findings (37, 38, 39, 40). The mechanism(s) governing cell-specific expression of the granins remains to be elucidated, although for the CgA gene, we (41, 42) and others (43, 44) have shown that sequences in the proximal promoter are important for basal transcription in neuroendocrine cells.

Because the precise role that CgA plays in the parathyroid cell is unclear, the consequences of altered CgA synthesis in the parathyroid gland are not known. Intracellularly, it has been suggested that by its ability to aggregate with some types of molecule but not others in the trans-Golgi network, CgA directs the sorting and packaging of peptide hormones and neurotransmitters to granules of the regulated secretory pathway in neuroendocrine cells (45). Indirect evidence for this comes from in vitro studies showing that under low pH and high Ca2+ conditions like those found in the trans-Golgi network adjacent to budding secretory granules, CgA coaggregates with peptide hormones such as PTH but excludes constitutively secreted proteins such as serum albumin (46). Extracellularly, several peptides contained within CgA, such as ß-granin [CgA-(1–113)] (47), CgA-(1–40) (48, 49), pancreastatin [porcine CgA-(240–288)] (50), and parastatin [porcine CgA-(347–419)] (51), have been shown to inhibit low Ca2+-stimulated secretion from cultured parathyroid cells. Addition of CgA antibodies to the medium of cultured parathyroid cells leads to increased PTH release from the cells (52). The mechanism of action of CgA-peptides on parathyroid cells is unknown, although it is assumed to be receptor-mediated. It is not known whether in vivo CgA acts in a predominantly intracellular or extracellular manner in the parathyroid cell. However, it should be noted that little processing of CgA to peptides occurs within the parathyroid cell (53, 54). Therefore, if CgA peptides are active on parathyroid cells in vivo, they are probably derived extracellularly or are released from neighboring nonparathyroid cells.

In summary, we have shown in vivo that increased serum 1,25-(OH)2D3 concentrations stimulate, and decreased concentrations are associated with reductions in parathyroid CgA gene expression. In mild CRI with reduced serum 1,25-(OH)2D3 levels, but with normocalcemia, parathyroid CgA mRNA levels are reduced, whereas those of PTH mRNA are increased.


   Acknowledgments
 
We thank Johanne Bourdon, Xinying Du, Lee Ehler, and Damian Wheeler for technical assistance with these studies; and Pamela Kirk, Carmen Ferrara-Wilson, and Debra Hamel for the preparation of the manuscript. We thank Dr. Milan Uskokovic of Hoffman LaRoche Inc., Nutley, New Jersey, for supplying 1,25-(OH)2D3.


   Footnotes
 
1 This work was supported by a grant from the Kidney Foundation of Canada and Grant MT-9315 from the Medical Research Council of Canada. E.S. was supported in part by the Royal Victoria Hospital Research Institute, and G.N.H. is the recipient of a scientist award from the Medical Research Council of Canada. Back

Received December 23, 1996.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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