(Hypertension. 1996;28:244-249.)
© 1996 American Heart Association, Inc.
Articles |
Dietary Sodium Intake Modulates Pituitary Proopiomelanocortin mRNA Abundance
the Divisions of Nephrology (H.M., K.-T.L., E.Y.L., M.H.H.) and Endocrinology (E.W., J.E.K.), San Francisco General Hospital, and Department of Medicine (H.M., K.-T. L., E.Y.L., E.W., J.E.K., M.H.H.), University of California San Francisco.
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Abstract |
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The pituitary prohormone proopiomelanocortin gives rise to melanocortins of
, ß, and 
primary structure in addition to corticotropin. Melanocortins have a variety of actions in mammals, and each is natriuretic. In particular, -melanocyte–stimulating hormone has been shown to mediate reflex natriuresis after acute unilateral nephrectomy. We examined whether this peptide could play a role in longer term adjustments in sodium balance by measuring plasma -melanocyte–stimulating hormone and corticotropin concentrations, as well as pituitary proopiomelanocortin mRNA abundance, in Sprague-Dawley rats ingesting either a low (0.07% NaCl) or high (7.5% NaCl) sodium diet. One week after the high sodium diet, plasma -melanocyte–stimulating hormone concentration was double the value seen in rats on the low sodium diet (158±5 [SE] versus 76±9 fmol/mL, P<.001), a change that was accompanied by a fivefold increase in plasma atrial natriuretic peptide concentration but no change in plasma corticotropin. Whole pituitary proopiomelanocortin mRNA abundance, measured with a probe to exon 3 of the rat proopiomelanocortin gene, was significantly increased after 1 week of the high sodium diet compared with the low sodium diet and increased further at 2 and 3 weeks. This increase occurred primarily in the neurointermediate lobe as demonstrated by in situ hybridization; the content of -melanocyte–stimulating hormone immunoreactivity was also increased in this lobe, but not the anterior lobe, after 1 week of the high sodium diet. These results demonstrate that high dietary sodium intake increases neurointermediate lobe proopiomelanocortin mRNA abundance compared with a very low sodium diet and also suggest that proopiomelanocortin is preferentially processed into -melanocyte–stimulating hormone rather than corticotropin. These observations consequently raise the possibility of a role for this peptide hormone system in the adjustments to a high salt diet.
Key Words: adrenocorticotropic hormone • hybridization • natriuretic peptides • rats • RNA • sodium, dietary • pituitary
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Introduction |
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The ACTH precursor POMC contains a 16-kD N-terminal portion that is highly conserved among mammals and gives rise to several peptides. The functions of these peptides are largely unknown. Among the peptides derived from this region of POMC is a 12–amino acid sequence flanked by dibasic amino acid cleavage sites and termed
-MSH because of homology with - and ß-MSH. -MSH possesses potent cardiovascular and renal actions that suggest it may play a role in circulatory regulation and body fluid balance.1 2 Low-dose infusions, either intravenously or directly into a renal artery, lead to natriuresis,3 4 whereas higher intravenous doses cause an acute increase in blood pressure and heart rate.5 6 These cardiovascular actions are thought to involve brain regions surrounding the anterior third ventricle of the rat7 and are mediated by stimulation of sympathetic nervous outflow8 through activation of vasopressinergic neurons.9 Mitchell et al10 have also shown that -MSH can activate supraoptic magnocellular neurons involved in vasopressin secretion. A hypotensive, bradycardic action of -MSH has been observed after microinjection into the nucleus of the tractus solitarius.11
The natriuretic actions of -MSH have not been fully characterized. The renal nerves are required because infusion of the peptide into the renal artery of acutely denervated kidneys did not increase UNaV.12 We have presented evidence that -MSH may be involved in the reflex natriuresis that occurs after acute reduction in functioning renal mass by unilateral nephrectomy13 14 or unilateral ureteral obstruction.14 Components in the reflex arc after acute unilateral nephrectomy include carotid sinus baroreceptors15 and the pituitary gland,4 16 and a role for renal afferent nerves has also been suggested.14 17 Thus, complex actions of -MSH could underlie acute adjustments in circulatory homeostasis by modulating sympathetic nervous outflow, vasopressin secretion, and UNaV.
Whether -MSH might also play a role in more long-term alterations in body fluid homeostasis is not known. Using electron microscopy, Duchen18 observed increased granularity of NIL cells in rats given 2% saline drinking water, and Howe and Thody19 reported an increase in NIL weight and NIL MSH content (measured by a frog skin bioassay) in rats also ingesting 2% NaCl drinking water. Elkabes and Loh20 identified alterations in mouse pituitary POMC mRNA as well as plasma ACTH and -MSH concentrations when a high sodium intake was achieved by substituting normal saline for drinking water. They concluded that their results could possibly reflect the response of the mice to the stress of the saline drinking water. We therefore set out to examine more specifically the relationship of plasma and pituitary -MSH and pituitary POMC mRNA to changes in sodium intake produced by a more physiological manipulation of dietary sodium content. Our results indicate that dietary sodium loading is accompanied by an increase in pituitary POMC message abundance, primarily in the NIL, and by an increase in NIL -MSH content and plasma -MSH concentration without a change in ACTH. They therefore indicate a specific effect of the high sodium diet on pituitary POMC mRNA levels, as well as the processing of POMC into -MSH, and further support the contention that this peptide participates in the maintenance of body fluid homeostasis.
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Animals
The protocols were approved by the University of California San Francisco Committee on Animal Research. Seventy-six male Sprague-Dawley rats (Bantin-Kingman, Fremont, Calif) weighing 260 to 280 g were maintained on rat chow as described below and tap water ad libidum with a 12-hour light/dark cycle. All rats were initially placed on a nutritionally complete LSD (0.07% NaCl, Ralston Purina). After 7 days, half the rats were changed to a nutritionally identical HSD (7.5% NaCl). Initial experiments measured plasma hormone concentrations after 1 week of HSD versus LSD; rats were killed by decapitation, and trunk blood was collected in ice-cold tubes containing 1 mg EDTA, 500 kallikrein inhibiting units aprotinin, and 50 µmol/L phenylmethylsulfonyl fluoride. The tubes were centrifuged in a refrigerated centrifuge (Sorvall model RC2-B, DuPont Medical Products) at 4000g (4°C) for 10 minutes, and the plasma was immediately separated and stored at -70°C. In subsequent experiments, rats were killed from each group at 1, 7, 14, and 21 days after HSD institution for determination of pituitary POMC mRNA or
-MSH contents. The day before death, some rats were placed in metabolic cages so urine could be collected for measurement of UNaV. Weight was measured weekly. Whole pituitary lobes were removed and either frozen in liquid nitrogen and stored at -70°C for subsequent RNA extraction or in situ hybridization or divided into AL and NIL and placed in 1N HCl for later radioimmunoassay of POMC peptide content.
RNA Isolation
Total pituitary cellular RNA was isolated with a commercial kit (RNAzol, Tel-test, Inc). Briefly, frozen pituitaries were homogenized with a Polytron (Brinkmann Instruments, Inc) in RNAzol B (2 mL per 100 mg tissue). One-tenth volume of chloroform was added to the homogenate, and the tube was shaken vigorously for 15 seconds and placed on ice for 15 minutes. This suspension was centrifuged at 12 000g (4°C) for 15 minutes, the aqueous phase was removed, and the RNA was precipitated by the addition of 1 vol isopropanol and centrifugation at 12 000g (4°C) for 15 minutes. The RNA pellet was rinsed twice with 75% ethanol (vol/vol), dried under vacuum, and resuspended in sterile water. RNA concentration was determined by standard UV absorbance (260/280 nm ratio >1.9), and RNA integrity was evaluated by agarose gel electrophoresis.21
Synthesis of Hybridization Probes
A POMC cRNA probe to exon 3 of the rat POMC gene was constructed from a POMC cDNA subcloned into the Sp64 vector (gift of J. Eberwine, University of Pennsylvania, Philadelphia). Probes were synthesized in a 20-µL transcription reaction containing l µg linearized template DNA; 40 mmol/L Tris-HCl, pH 8.0; 6 mmol/L MgCl2;10 mmol/L dithiothreitol; 2 mmol/L spermidine; 10 mmol/L NaCl; 0.5 mmol/L each of ATP, GTP, and UTP; and 12 µmol/L CTP with 50 µCi of [32P]CTP, 20 U RNAsin, and 7 U polymerase (Sp6). The reaction mixture was incubated at 37°C for 60 minutes, and the DNA template was removed by digestion with 2 U RNAse-free DNAse for 15 minutes at the same temperature. The reaction was stopped by the addition of 10 mmol/L EDTA. Labeled cRNA probes were purified with QuickSpin G-Sephadex RNA columns (Boehringer Mannheim).
An oligomer (5'-AAGGATCAGAGTAGTGTATTTCACC-3') to 28S rRNA was synthesized (Genosys Biotechnologies, Inc) and end-labeled with a terminal transferase reaction kit (DuPont-NEN). Labeled oligomer probes were purified with NucTrap columns according to the manufacturer's protocol (Stratagene).
A POMC DNA probe was nick-translated according to the kit protocol (Stratagene Nick Translation System). Briefly, 5 µL of nick translation buffer, 4 µL of dNTP mixture (excluding dCTP), 1 µL of 0.5 µg DNA (POMC), 6 µL translation-grade water, 2 µL DNA polymerase (0.6 U/µL), 2 µL DNAse 1 (0.2 U/µL), and 10 µL of [-33P]dCTP were mixed together on ice. The mixture was incubated at 14°C for 2 hours, and the reaction was stopped with 5 µL of 250 mmol/L EDTA. The probe was purified with NucTrap soybean trypsin inhibitor push columns (Stratagene) and was ethanol-precipitated with 1/10 vol of 3 mol/L sodium acetate (pH 5.5), 2 vol of 100% ethanol, and 30 µg tRNA overnight at -20°C. The precipitate was recovered by centrifugation at 12 000g (4°C) for 15 minutes.
Northern Blot Hybridization
Total RNA was denatured in 1 mol/L glyoxal, 50% dimethyl sulfoxide, 10 mmol/L sodium phosphate, pH 7.0, and then electrophoresed through a horizontal 1% agarose gel. The RNA was transferred to a nylon membrane (Hybond-N, Amersham Corp). Membranes were prehybridized at 60°C in 50% formamide, 3x SSC, 10x Denhardt's solution, 20 mmol/L Tris (pH 7.6), 10 mmol/L EDTA (pH 8.0), 200 µg/mL sheared denatured salmon sperm DNA, and 0.2% SDS. Hybridization was carried out for 12 hours at 60°C with an identical solution containing 2x106 cpm/mL of 32P-labeled cRNA POMC probe. After hybridization, the membranes were washed three times each with 2x SSC, 0.2% SDS and 0.2x SSC, 0.2% SDS at 60°C to eliminate nonspecific binding of the probe. Autoradiographs were obtained by exposure to Kodak XOMAT-AR x-ray film with double intensifying screens at -70°C for 12 to 96 hours.
Potential RNA loading artifacts were evaluated by stripping the POMC probe from the membranes and hybridizing with the 28S ribosomal probe. The membranes were prehybridized in a solution containing 50% formamide, 5x SSC, 10x Denhardt's solution, 20 mmol/L Tris (pH 7.6), 10 mmol/L EDTA (pH 8.0), 200 µg/mL sheared denatured salmon sperm DNA, and 0.2% SDS. Hybridization was carried out in an identical solution containing 2x106 cpm/mL 28S ribosomal probe for 12 hours at 42°C. Membranes were washed as before except the temperature used was 50°C. Autoradiographs were obtained as described above, and all were subsequently scanned with a laser densitometer (Molecular Dynamics Personal Densitometer). Pixel density was quantified with ImageQuant software version 3.3 (Molecular Dynamics).
In Situ Hybridization
Whole pituitaries were harvested and embedded in polyvinyl alcohol and polyethylene glycol (OCT) in aluminum foil boats and stored frozen at -70°C. Tissue sections (6 to 8 µm) were cut with a cryostat and thaw-mounted onto positively charged slides. Sections were fixed in paraformaldehyde (4%) in phosphate-buffered saline for 8 minutes and then serially rinsed in phosphate-buffered saline (1 to 2 minutes) two times, followed by a single 1-minute rinse in water. The sections were then dehydrated in ethanol (50%, 70%, 90%, and 100%), sealed in light-tight plastic boxes, and stored at -80°C until needed. Slides were removed from -80°C storage, placed in 100% ethanol at room temperature, and air-dried, after which each section was encircled by a hydrophobic marking pen (Kiyota International Inc). Sections were prehybridized in 50 µL prehybridization mix consisting of 600 mmol/L NaCl, 10 mmol/L Tris (pH 7.4), 0.05 mg/mL tRNA, 0.5 mg/mL DNA, 0.02% polyvinylpyrrolidone, 0.002% bovine serum albumin, 1 mmol/L EDTA, 50% formamide, and water and covered with parafilm coverslips. Slides were put in damp utility boxes, covered tightly, and incubated overnight at 37°C. The prehybridization mix was replaced with identical solution containing 105 cpm of the nick-translated POMC probe. The slides were put back in the humidified utility boxes and incubated at 37°C for 48 hours. Slides were put in a multislide holder, and the sections were rinsed two times for 5 minutes in 2x SSC and 0.5% sodium pyrophosphate. They were then rinsed overnight in 0.5x SSC and 0.5% sodium pyrophosphate. Tissue sections were dehydrated with an alcohol gradient, dried, and exposed to x-ray film (Hyperfilm-MP, Amersham Corp). Films were developed after 24 and 48 hours. The autoradiographs were scanned with a laser densitometer, and pixel density was quantified. Slides were also exposed to emulsion autoradiography with photographic emulsion (Eastman Kodak) and developed after 48 hours. Sections were inspected with a dark-field microscope.
Radioimmunoassays
Plasma samples underwent extraction with Sep-Pak C18 chromatography cartridges (Waters Associates). The cartridges were prepared by wetting with 3 mL of solvent A (acetonitrile/water/trifluoroacetic acid [TFA], 80:19.9:0.1) and with 3 mL of 0.1% TFA. The plasma aliquot (3 mL) was thawed on ice and passed through the cartridge, which was then washed with 10 mL of 0.1% TFA and eluted with solvent A. Eluates were lyophilized and stored at -70°C. Whole pituitaries were dissected into AL and NIL and immediately put in 100 µL of 1N HCl. Each specific lobe was homogenized and centrifuged, and the supernatant was stored at -70°C for radioimmunoassay. The pellet was stored at 4°C for measurement of protein content.
Our -MSH radioimmunoassay uses an antiserum recognizing an epitope within the sequence POMC-(51-62). The characteristics of this assay have been described13 14 ; its sensitivity is 1 fmol per tube. Synthetic 2-MSH was used as standard and tracer. The antiserum recognizes the C-terminal portion of the peptide corresponding approximately to the sequence POMC-(56-62) and shows less than 1% cross-reactivity with ACTH or - or ß-MSH. ACTH and ANP were assayed with commercially available kits (Peninsula Laboratories); assays were carried out according to the manufacturer's instructions. Protein content of pituitary lobes was measured by the bicinchoninic acid protein assay (Pierce Biochemicals). Pituitary levels of -MSH were expressed as femtomoles per microgram protein.
Statistical Analysis
Statistical comparisons between groups were made with Student's t test for unpaired data; when multiple comparisons were needed, one-way ANOVA was used. Results are expressed as mean±SE. The null hypothesis was rejected with an value of .05 (P<.05).
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Results |
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UNaV in the LSD rats was very low, whereas the HSD rats excreted much more sodium during the 3-week period of the study (Table
). HSD rats also had much higher urine volumes (Table). After 1 week of the diets, HSD rats had a significantly greater concentration of both ANP and -MSH immunoreactivity in plasma compared with LSD rats. The immunoreactive -MSH level was 158±5 fmol/mL in the HSD group and 76±9 in the LSD group (P<.001); ANP values were even more widely divergent between the two groups (Fig 1). ACTH concentration did not differ between the groups (Fig 1), indicating that the HSD had a preferential effect to increase plasma -MSH concentration without an effect on plasma ACTH. As shown in Fig 2, the abundance of whole pituitary POMC mRNA (corrected for 28S signal) increased with time in HSD rats. This increase was not statistically significant after 1 day (data not shown), but after 1 week, HSD rats had a significantly greater POMC message abundance than LSD rats (P<.05). After 2 and 3 weeks of the diet, the difference between the groups became even greater. Signal intensity in the pituitaries of LSD rats did not change at any time. This increase in whole pituitary POMC mRNA occurred primarily in the NIL, as demonstrated by in situ hybridization. At 1 week of the HSD, granularity in HSD rats was markedly increased in the NIL compared with that in LSD rats (Fig 3). A significant but small increase was observed in the AL (Fig 3).
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The content of -MSH in the NIL of rats after 2 weeks on the LSD was 2.37±0.40 pmol/µg protein but was significantly increased in the NIL of rats on the HSD for 1 week (4.86±0.83 pmol/µg protein, P<.02; Fig 4). -MSH in the AL did not differ between the LSD and HSD groups (0.37±0.04 and 0.33±0.03 pmol/µg protein, respectively; P=NS). In these experiments, plasma immunoreactive -MSH concentration was 54.3±11.6 fmol/mL during the LSD and 82.9±6.2 during the HSD (P=.036); the corresponding values for ACTH were 116.7±7.1 and 99.1±4.3 fmol/mL (P<.05). Thus, as observed in plasma, the HSD increased NIL -MSH content compared with the LSD.
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Discussion |
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Maintenance of extracellular fluid volume constancy in the face of fluctuating dietary sodium intake occurs through appropriate changes in the rate of UNaV. Classically, the reduction in UNaV that occurs after an abrupt decrease in dietary sodium content has been described as resulting from activation of antinatriuretic mechanisms such as efferent renal sympathetic nerves, the renin-angiotensin system, and aldosterone. More recently, attention has also focused on the suppression of a natriuretic mechanism, that is, secretion and action of ANP.22 The reduction in UNaV after an abrupt decrease in dietary sodium intake in humans was analyzed by Strauss and associates23 and found to follow an exponential decline with a time constant of roughly 24 hours; therefore, sodium balance at the new, low level of sodium intake was achieved in 4 to 5 days. Although less well studied, it has always been presumed that the renal response to an abrupt increase in dietary sodium intake is the mirror image, that is, suppression of antinatriuretic and activation of natriuretic mechanisms.23 Limited experimental data suggest that this may be an inadequate description,24 25 perhaps because of activation of other natriuretic pathways that follow a different time course. A number of natriuretic factors have been identified,26 but the only one to date convincingly related to the maintenance of salt balance is ANP, and even its role is controversial.27 28
The possibility that -MSH could serve as a natriuretic peptide was suggested from observations demonstrating its natriuretic action in picomolar concentrations in plasma3 13 and the evidence supporting its role in mediating natriuresis after acute unilateral nephrectomy.13 14 29 We undertook the present studies in an effort to determine whether the peptide could be shown to be modulated in parallel with more chronic changes in UNaV. In rats exposed to the HSD for 1 week, plasma immunoreactive -MSH concentration was twice the value seen in rats maintained on the LSD, a response consistent with its putative role as a natriuretic hormone. Such an increase in circulating -MSH levels could result from an increase in the secretion of the peptide, most likely from the pituitary, or a decrease in its metabolic clearance rate, or both. Although we did not measure the metabolic clearance of -MSH in these studies, we did obtain strong evidence for an increase in its secretion. First, there was a clear-cut increase in mRNA of the -MSH precursor POMC at 1 week of the HSD, a time when plasma peptide concentration was elevated. It is generally accepted that an increase in mRNA abundance can usually be equated with an increase in the synthesis of the encoded protein. Second, this increase in whole pituitary POMC mRNA was accompanied by an increase in -MSH immunoreactivity in the NIL, suggesting an increase in the synthesis of the peptide in this lobe. The overall increase in pituitary POMC mRNA was confined largely to the NIL, paralleling the increase in -MSH immunoreactivity in this lobe seen after 1 week of the HSD. On the other hand, no change in plasma immunoreactive ACTH concentration occurred in response to the HSD. In aggregate, these observations strongly point to an increase in -MSH synthesis and secretion by the NIL to account for our finding of an increase in plasma -MSH immunoreactivity after 1 week of the HSD. They may also help to rationalize the somewhat divergent findings of Elkabes and Loh,20 who observed fluctuations in pituitary POMC mRNA and plasma peptide concentrations in mice given normal saline drinking water. In our experiments, sodium intake was manipulated by the more physiological (and less stressful) approach of altering the sodium content of the food.
The peptide content in AL and NIL also leads to the conclusion that the NIL is the most likely site for this increased -MSH synthesis and secretion. Our Northern analysis was carried out with RNA harvested from whole pituitaries and consequently could not distinguish whether the AL, the NIL, or both were responsible for the increase in POMC mRNA in HSD rats. However, in situ hybridization clearly defined the NIL as the predominant site of this increased POMC mRNA, a conclusion further supported by the demonstration of increased -MSH immunoreactivity in NIL but not AL. These findings suggest that the effect of the HSD on pituitary POMC production and metabolism is specific to this lobe.
Processing of POMC in the two lobes differs in that cleavage products in AL are primarily ACTH and ß-lipotropin, whereas in NIL, further processing into -MSH and ß-endorphin and -lipotropin occur. Currently, it is thought that these differing cleavage products reflect the activities of two different processing enzymes, proconvertase 1 in the AL and proconvertase 2 in the NIL.30 The action of either of these enzymes on the N-terminus of POMC has not been extensively studied; the demonstration of increased -MSH immunoreactivity in the NIL of HSD rats suggests that smaller N-terminal peptides as well as those arising from the C-terminal portion of POMC may be the posttranslational products in this lobe.
This possibility gains further support from the observation in our studies that no change in ACTH concentration in plasma could be demonstrated in HSD rats at a time when -MSH immunoreactivity was increased in both plasma and the NIL. Since ACTH is not a normal cleavage product in NIL, giving rise instead to -MSH [ACTH-(1-13)], our results could be explained if the HSD, compared with the LSD, led to an increase in POMC synthesis in the NIL, where it was subsequently processed into -MSH and perhaps other smaller POMC-derived peptides. Both - and ß-MSH are also known to possess natriuretic properties, and it will be important to determine whether their content in NIL and plasma is also increased in response to the HSD or whether the HSD effect on POMC processing is specific to the -MSH secretory product. POMC metabolism and secretion of its cleavage products in the NIL are under tonic dopaminergic inhibition; and haloperidol, a dopamine receptor antagonist, and bromocriptine, a dopamine agonist, increase and decrease, respectively, POMC, proconvertase 1, and proconvertase 2 mRNA levels in this lobe.31 It is possible that these dopaminergic agents could be used to study the importance of -MSH in the maintenance of sodium balance.
The relevance of these observations to humans is not yet established. In normal adults, the pars intermedia is usually difficult to discern histologically, but immunocytochemical and histochemical staining identify cells with characteristics of melanotrophs in the human pituitary,32 33 34 and -MSH immunoreactivity has been measured in human plasma.35 36 Thus, it is plausible to entertain the hypothesis that this system could be involved in the regulation of sodium metabolism in humans. Further clinical studies will be necessary to examine this hypothesis.
In summary, our results show that pituitary POMC mRNA abundance and plasma -MSH concentration are increased in rats ingesting an HSD compared with an LSD. Given the natriuretic properties of this peptide, the data suggest the possibility that these changes are linked to the adjustment in sodium excretion necessary for maintenance of sodium balance in the face of a large increase in sodium intake.
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Acknowledgments |
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These studies were supported by grants DK 31623 and HD 29562 from the National Institutes of Health, and by Grants-in-Aid 89-1124 and 94-1229 from the American Heart Association. Dr Mayan was supported by training stipends from the American Physicians Fellowship and the Division of Clinical Pharmacology at UCSF.
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Footnotes |
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Reprint requests to Michael H. Humphreys, MD, Box 1341, SFGH, University of California San Francisco, San Francisco, CA 94143. E-mail mhhsfgh@itsa.ucsf.edu.
Portions of this work have appeared previously in abstract form (Hypertension. 1993;22:417; J Am Soc Nephrol. 1994;5:545).
Received October 9, 1995;
first decision November 9, 1995; first decision November 9, 1995; first decision March 28, 1996;
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