Vascular Biology and Hypertension Program, Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294
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ABSTRACT |
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Atrial natriuretic
peptide (ANP) has negative modulatory effects on a variety of
pathophysiological mechanisms; i.e., it inhibits hypoxia-induced
pulmonary vasoconstriction and vascular remodeling and facilitates
natriuresis and vasorelaxation in NaCl-supplemented subjects. We have
previously demonstrated organ-selective potentiation of ANP in the
pulmonary circulation of hypoxia-adapted animals by local
downregulation of its clearance receptor (NPR-C; Li H, Oparil S, Meng
QC, Elton T, and Chen Y-F. Am J Physiol Lung Cell Mol
Physiol 268: L328-L335, 1995). The present study tested the hypothesis that NPR-C expression is attenuated selectively in kidneys
of NaCl-supplemented subjects. Adult male wild-type (ANP+/+) and
homozygous mutant (ANP/
) mice were studied after 5 wk of normal or
high-salt diets. Mean arterial pressure (MAP) and left (LV) and right
ventricular (RV) mass were greater in ANP
/
mice than in ANP+/+ mice
fed the normal-salt diet; salt supplementation induced increases in
plasma ANP in ANP+/+ mice and in MAP and LV, RV, and renal mass in
ANP
/
mice but not in ANP+/+ mice. NPR-C mRNA levels were
selectively and significantly reduced (>60%) in kidney, but not in
lung, brain, LV, or RV, by dietary salt supplementation in both
genotypes. NPR-A mRNA levels did not differ among diet-genotype groups
in any organ studied. cGMP content was significantly increased in
kidney, but not in lung or brain, by dietary salt supplementation in
both genotypes. These findings suggest that selective downregulation of
NPR-C in the kidney in response to dietary salt supplementation may
contribute to local elevation in ANP levels and may be functionally
significant in attenuating the development of salt-sensitive hypertension.
salt-sensitive hypertension; atrial natriuretic peptide; clearance receptor; atrial natriuretic peptide knockout mice; kidney
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INTRODUCTION |
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ATRIAL NATRIURETIC PEPTIDE (ANP) is a peptide hormone that has potent natriuretic, diuretic, vasodilator, sympatholytic, and renin- and aldosterone-suppressing activities and is involved in the regulation of volume and electrolyte balance and blood pressure (3-5, 25). The biological functions of ANP are mediated through activation of the NPR-A receptor and increases in intracellular cGMP (6). Circulating levels of ANP are regulated by binding to and inactivation by NPR-C, a membrane-bound receptor that functions as a clearance receptor to eliminate ANP from the circulation (16, 19), as well as hydrolysis by neutral endopeptidase 24.11 (NEP) (7).
Several lines of evidence indicate that ANP is involved in the pathogenesis of salt-sensitive hypertension (29). Chronic blockade of endogenous ANP with a monoclonal antibody accelerates the development and exacerbates the severity of hypertension in stroke-prone, spontaneously hypertensive rats (SHR-SP) and DOCA-salt hypertensive rats (8). Dietary salt supplementation in normotensive salt-resistant rats is associated with increased plasma ANP levels (11), whereas salt-sensitive SHR do not increase plasma ANP levels appropriately in response to dietary NaCl supplementation, thus failing to mount a natriuretic response and normalize blood pressure in the presence of dietary NaCl stress (11, 13). Furthermore, administration of either exogenous ANP or the NEP inhibitor SCH-34826, which protects endogenous ANP from hydrolysis, prevents salt-sensitive hypertension in SHR (12).
NPR-C accounts for the overwhelming majority of ANP binding sites in
most tissues, including kidney, lung, and brain (16), and
plays an important role in ANP clearance. Blocking NPR-C with the
selective antagonist C-ANP4-23 markedly increases
(~3-fold) circulating ANP levels (19) and attenuates
hypoxia-induced pulmonary hypertension in the rat (10).
Furthermore, the half-life of ANP in the circulation has been shown to
be two-thirds longer in mice with homologous deletion of the NPR-C gene
(Npr3/
) compared with wild-type mice (21).
We have previously demonstrated that NPR-C, but not NPR-A, gene expression is selectively downregulated in the lungs of rats and mice in response to the stress of hypoxia (17, 27). This phenomenon was found to be mediated by overexpression of tyrosine kinase-activating growth factors, such as acidic fibroblast growth factor (FGF-1), and was seen even in the absence of ANP gene expression (28). We hypothesize that selective downregulation of NPR-C expression in lung in the setting of hypoxia may contribute to the increase in circulating ANP levels seen under hypoxic conditions and may enhance the vasodilator effects of ANP in lung, thus modulating hypoxic pulmonary vasoconstriction/hypertension.
The present study tested the hypothesis that, under the stress of
dietary salt supplementation, NPR-C gene expression is selectively downregulated in kidneys of wild-type (ANP+/+) mice and mice with insertion inactivation of the ANP gene (ANP/
). We hypothesize that
local potentiation of ANP [and possibly other natriuretic hormone(s)]
protects against the development of salt-sensitive hypertension by this mechanism.
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METHODS |
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Transgenic mice.
Mice with a mutated pro-ANP gene (Nppa), ANP/
,
generated by John et al. (14), were used (Jackson
Laboratory, Bar Harbor, ME). The animals were raised from our resident
colony, which was founded with pathogen-free breeding pairs. The
genotypes were identified by PCR assay of genomic DNA from tail snips
after the animals were weaned. All mice were housed in groups of three
to four per cage and maintained at a constant humidity (60 ± 5%), temperature (24 ± 1°C), and light cycle (6 AM-6 PM).
All protocols were approved by the Institutional Animal Care and Use
Committee at the University of Alabama at Birmingham and were
consistent with the Guide for the Care and Use of Laboratory
Animals [DHEW Publication No. (NIH) 85-23, revised 1985].
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High-salt dietary regimen, hemodynamic measurement, and tissue
collection.
Male ANP+/+ and ANP/
mice (9-10 wk old), weighing 25-30
g, were used in this study. Half of the mice in each genotypic group (ANP+/+ and ANP
/
) were placed at random on a high-salt diet (3.2%
Na+, 4.8% Cl
, and 0.68% Ca2+,
Teklad diet 92012, Harlan-Teklad, Madison, WI) for 5 wk, whereas the
other half remained on the standard salt diet (0.27% Na+,
0.28% Cl
, and 0.77% Ca2+, Teklad diet 8746, Harlan-Teklad). Food and water were available ad libitum throughout the
study. Five weeks after initiation of the special diet, mice were
weighed and anesthetized with a mixture of ketamine (10 mg/100 g im)
and xylazine (1.5 mg/100 g im). A PE-10 catheter was implanted into the
left common carotid artery through the left external carotid artery.
Twenty-four hours after surgery, the arterial catheter was connected to
a pressure transducer coupled to a Biopac model MP100 data-acquisition
unit with output to a PC sampling at 100 Hz and using Acknowledge
Software (Biopac Systems, Santa Barbara, CA). MAP and heart rate (HR)
were measured simultaneously in conscious mice.
RNA isolation and Northern blot analysis. Total RNA was extracted by the guanidine thiocyanate method, and Northern analysis was performed as previously described (17), using 32P-labeled selective cDNA probes for ANP (courtesy of Dr. R. Wiegand at Monsanto, St. Louis, MO) and cDNA probes for NPR-A and NPR-C that had been generated in our laboratory by RT-PCR, using lung RNA as the template as previously described (17). Between each reprobing, 32P-labeled cDNA was stripped off the membrane by pouring boiling 0.1× standard sodium citrate, 0.1% SDS onto the membrane and shaking for 20 min at room temperature. To quantitate the amount of RNA loaded, blots were stripped as above and rehybridized with a control probe, a 32P-labeled GAPDH probe. Autoradiographic signals were scanned with an optical densitometer (GS-670 Imaging Densitometer, Bio-Rad, Hercules, CA). The results were expressed as the ratios of specific mRNA to GAPDH mRNA.
ANP and cGMP measurements. Plasma ANP content was measured by RIA with ANP RIA kits (Peninsula Laboratories, Belmont, CA) after extraction with Sep-Pak C18 cartridges (Waters Associates, Milford, MA) as previously described (27). Tissue cGMP content was measured by RIA with cGMP RIA kits (DuPont NEN Research Products, Boston, MA) as previously described (27). The sensitivities of the ANP and cGMP RIAs are 2 pg and 25 fmol/assay tube, respectively.
Statistical analysis. Results are expressed as means ± SE. Statistical analyses were carried out using the CRUNCH statistical package (CRUNCH Software, Oakland, CA) on an IBM PC-compatible computer. The data were analyzed by two-way ANOVA to test for separate and combined effects of genotypes and high-salt diet on tissue weight, blood pressure, heart rate, plasma ANP, and tissue mRNA levels. If ANOVA results were significant, an unpaired Student's t-test was used to test the effects of genotypes or high-salt diet on the above variables. Differences were reported as significant if the P value was <0.05.
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RESULTS |
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Body weights in the normal-salt groups did not differ between
genotypes (Table 1). ANP+/+, but not
ANP/
, mice fed the high-salt diet had slightly but significantly
lower body weights than their normal salt controls. MAP of the ANP
/
mice was significantly greater than that of ANP+/+ mice on the
normal-salt diet (Table 1, Fig.
2A), and dietary salt
supplementation produced significant increases in MAP in ANP
/
(22.2 ± 4.3 mmHg or 20.6 ± 4.0% increase, P < 0.05, compared with normal-salt ANP
/
) but not
in ANP+/+ mice (7.6 ± 3.8 mmHg or 8.3 ± 4.2% increase,
P > 0.1, compared with normal-salt ANP+/+). No
differences in HR between genotypes or diet groups were observed (Table
1).
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As anticipated, plasma ANP and steady-state ventricular (LV and RV) ANP
mRNA levels were barely detectable in either normal- or high-salt-fed
ANP/
mice (Fig. 2, B, D, and F).
Salt supplementation significantly increased plasma ANP and LV, but not
RV, ANP mRNA levels in ANP+/+ mice. ANP
/
mice on the normal-salt
diet had heavier atria (Table 1), LV (Fig. 2C), RV (Fig.
2E), and LV+RV (Table 1) than ANP+/+ mice. The high-salt
diet was not associated with significant enlargement of atria, LV, or
RV in ANP+/+ mice but was associated with significant increases in
atrial, LV, RV, and LV+RV weights in ANP
/
mice. The increases in
atrial, LV, RV, and LV+RV weights were significantly greater in
ANP
/
mice than in ANP+/+ fed the high-salt diet (P < 0.05; 2-way ANOVA showed a significant interaction between salt and
ANP genotype on atrial, LV, RV, and LV+RV weights). Kidney, brain, and
lung weights did not differ between the two mouse genotypic groups on
the normal-salt diet. The high-salt diet increased kidney, but not
brain or lung, weights in ANP
/
mice.
Steady-state NPR-C mRNA levels were significantly lower in both kidneys
(Fig. 3A) and lungs (Fig.
3C) of ANP/
mice compared with ANP+/+ mice on the
normal-salt diet. Dietary salt supplementation was associated with
major (68 ± 9 and 60 ± 7% in ANP+/+ and ANP
/
mice,
respectively) reductions in NPR-C expression in kidney only (Fig.
3A). NPR-C expression in lung was not sensitive to salt intake (Fig. 3C). NPR-C expression in heart (LV and RV)
(Fig. 3, E and G) and brain (Fig. 3I)
did not differ between genotypes or diet groups. Unlike NPR-C,
steady-state NPR-A mRNA levels in all organs examined did not differ
between genotypes or dietary regimens (Fig. 3, B,
D, F, H, and J).
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Kidney cGMP content in the normal-salt groups did not differ between
genotypes (Fig. 4). Dietary salt
supplementation was associated with significant increases in kidney
cGMP content in both groups. The increases in kidney cGMP content were
significantly greater in ANP+/+ mice than ANP/
mice fed the
high-salt diet (P < 0.05; 2-way ANOVA showed a
significant interaction between salt and ANP genotype) (Fig.
4A). cGMP content in lung (Fig. 4B) and brain
(Fig. 4C) did not differ between genotypes or diet groups.
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DISCUSSION |
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The major finding of the present study was that dietary salt
supplementation was associated with a selective reduction in steady-state NPR-C mRNA levels in kidney of ANP+/+ and ANP/
mice. Major (> 60%) reductions in renal NPR-C mRNA were seen in both
genotypes despite major differences in circulating ANP levels, steady-state ANP mRNA expression, and MAP, indicating that the high-salt-induced downregulation of NPR-C expression in kidney is
independent of endogenous ANP and blood pressure levels.
The finding that expression of NPR-C is selectively reduced in kidneys
of both ANP+/+ and ANP/
mice fed a high-NaCl diet is in agreement
with previous reports by Nagase et al. (23). They
demonstrated that NPR-C gene expression was selectively reduced in the
kidney by chronic salt loading (8% NaCl diet for 4 wk) in both Dahl
salt-sensitive (DS) and salt-resistant (DR) rats, whereas expression of
NPR-A and NPR-B was not altered. The reduction in renal NPR-C mRNA
levels in response to salt supplementation was greater in DS (
53%)
than in DR rats (
28%). However, because the plasma ANP levels were
significantly increased in salt-loaded DS rats, but not in salt-loaded
DR rats, the above-mentioned investigators could not determine whether
the downregulation of NPR-C gene expression was caused by a
ligand-mediated mechanism. The present study demonstrated that the
selective downregulation of NPR-C expression in kidney of
salt-supplemented subjects is independent of endogenous ANP levels.
Our present findings are consistent with previous observations in
animal models and humans that ANP modulates blood pressure and protects
against the development of salt-sensitive hypertension. Studies from
our own laboratory (11-13) demonstrated that
high-salt-diet-induced ANP secretion induces vasodilation and
natriuresis that modulate the development of salt-sensitive
hypertension in SHR. John et al. (14) and Melo et al.
(22) have demonstrated that ANP/
mice manifest
increases in blood pressure in response to dietary salt
supplementation. Furthermore, NPR-A null mice fed either low (0.008%
NaCl)-, normal (0.7% NaCl)-, or high (8% NaCl)-salt diets have
elevated blood pressures compared with wild-type controls (18). Conversely, transgenic mice that overexpress ANP are
characterized by markedly decreased arterial pressure
(26), whereas NPR-C null mice exhibit a prolonged
half-life of circulating ANP and decreased blood pressure
(21). The relevance of these observations to human
hypertension is demonstrated by our previous finding that, in
NaCl-sensitive hypertensive African-Americans, a high-NaCl diet causes
an increase in arterial pressure and, paradoxically, a decrease in
plasma ANP (1). Thus a deficiency in circulating ANP under
conditions of dietary NaCl stress likely contributes to
salt-sensitive hypertension in humans due to the lack of this important
natriuretic/vasodilatory factor.
Approximately 99% of all ANP receptors in kidney are NPR-C, and these are localized mainly in the vascular and glomerular structures of the cortex, particularly in the podocytes of glomerular cells (16, 19, 23). The direct renal actions of ANP to promote natriuresis and diuresis are mediated through relaxation of preconstricted renal vasculature and increases in renal blood flow and glomerular filtration rate (2). The present observation of selective reductions in NPR-C in kidney under conditions of dietary salt supplementation suggests a mechanism of locally regulating ANP concentrations to facilitate natriuresis/diuresis and the maintenance of volume homeostasis. Reductions in NPR-C density on the surface of ANP target cells, such as kidney vessels and glomeruli, would tend to retard the clearance of ANP from the renal circulation and thus increase the local availability of ANP to the biologically active NPR-A receptor, which is not downregulated during salt supplementation, leading to augmented vasodilator and natriuretic/diuretic effects. Guanylate cyclase-coupled NPR-A receptors are expressed in renal vessels, glomeruli, and papillae (20, 23), so the ANP that is potentiated by local downregulation of NPR-C can stimulate natriuresis/diuresis at both vascular and tubular levels.
The present finding that the cGMP content of the kidney, but not of the
lung and brain, of high-salt-fed ANP+/+ mice was significantly increased (>5-fold) compared with ANP+/+ mice on the normal-salt diet
provides further evidence that the downregulation of NPR-C potentiates
the biological effects of ANP in kidney. This inhomogeneity of the cGMP
response among target organs suggests that the increase in renal cGMP
levels was not simply a consequence of the doubling of plasma ANP seen
during dietary salt supplementation. Interestingly, the cGMP content of
kidneys of high-salt-fed ANP/
mice was also slightly but
significantly increased. Our interpretation is that the dietary salt
supplementation-induced downregulation of NPR-C may also potentiate the
stimulatory effect of B-type natriuretic peptide (BNP) on cGMP
production in the kidney in both genotypes. BNP has cardiovascular
effects similar to those of ANP and, like ANP, acts through the NPR-A
and NPR-B receptors to enhance intracellular cGMP
(4-6). It has been postulated that ANP and BNP
participate in a complementary "dual-peptide system" to modulate
vascular responses and intravascular fluid homeostasis and that BNP may act as an emergency molecule against ventricular overload
(4-6). If this were the case, it might be expected
that when ANP is deficient or lacking, BNP synthesis would be increased
and compensate for the lack of ANP in the present model. A limitation
of the present study is the inability to measure BNP. Mouse BNP antigen
could not be measured because of the unavailability of a selective
antibody for mouse BNP. Future studies in our laboratory are needed to address this deficiency.
The present findings and our previous studies in hypoxia-adapted animals have shown that ANP levels can be regulated locally in the target organs, thereby allowing the function of the natriuretic peptide system to be tailored to specific local needs. We have previously demonstrated that steady-state NPR-C mRNA expression is selectively downregulated in the lungs of hypoxia-adapted rats (17) and mice (27) in association with increased circulating levels of ANP. In contrast, mRNA levels of NPR-A and NPR-B are unchanged or increased in lungs under these conditions. The reduction in NPR-C in the hypoxic lung retards the clearance of ANP and allows more ANP to bind to biologically active NPR-A in the pulmonary circulation, thereby activating guanylate cyclase, increasing cGMP production, relaxing preconstricted pulmonary vessels, reducing pulmonary arterial pressure, and attenuating the development of hypoxia-induced pulmonary hypertension and vascular remodeling.
The cellular/molecular mechanisms by which NPR-C is regulated have
received considerable attention in our laboratory and others. Downregulation of NPR-C in tissues has been attributed to elevated ANP
levels in the circulation, which stimulate increased cGMP production
through the activation of NPR-A and guanylate cyclase (16). However, our experience with the ANP/
mouse
indicates that NPR-C expression is reduced selectively in critical
target organs of mice subjected to stress conditions (e.g., hypoxia, dietary salt supplementation) in the complete absence of circulating ANP (27). Furthermore, we recently demonstrated that
neither ANP nor cGMP in high concentrations reduced NPR-C gene
expression in pulmonary arterial smooth muscle cells (PASMCs) in vitro
(28).
In contrast, a variety of growth factors, including fibroblast growth
factors (FGF-1 and FGF-2), protein kinase A, protein kinase C, and
-adrenergic agonists (9, 16, 24, 27), have been shown
to regulate ANP receptors in tissues. We have recently shown that
FGF-1, FGF-2, and platelet-derived growth factor (PDGF)-BB induce rapid
dose- and time-dependent reductions in NPR-C mRNA expression in PASMCs
in vitro (28). The rapid (within 1 h) reduction in
NPR-C mRNA levels observed in this study in response to very low
concentrations (1 ng/ml to 40-60 pM) of FGF-1, FGF-2, and PDGF-BB
suggests that these growth factors could be physiological regulators of
NPR-C gene expression in vivo. Studies using inhibitors of signal
transduction pathways indicate that the inhibitory effects of FGF and
PDGF on NPR-C mRNA expression are mediated through activation of
membrane tyrosine kinase receptors and intracellular
Ras-Raf-mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase-MAPK signaling transduction pathways. Whether these regulators are involved in the high-salt-loading-induced downregulation of NPR-C gene expression in kidney deserves further investigation.
Other mechanisms adduced to explain the selective downregulation of NPR-C in kidneys of mice fed a high-salt diet include the direct effect of NaCl on NPR-C gene expression. Katafuchi et al. (15) reported that the NPR-C levels in cultured bovine carotid artery endothelial cells are sensitive to changes in the salt concentration of the culture medium. High-NaCl (50 mM) medium induced a marked reduction in the number of NPR-C, whereas NPR-A density was not affected by the treatment. However, these authors did not carry out further investigations to reveal the signaling mechanism(s) by which NaCl-mediated alterations in NPR-C expression occur.
In summary, this study provides evidence that chronic oral salt supplementation can selectively downregulate renal NPR-C gene expression independently of changes of ANP levels and expression of NPR-A. Downregulation of NPR-C likely represents an adaptation aimed at reducing ANP clearance from the circulation, thus enhancing the vasodilator and natriuretic effects of ANP in the kidney and mitigating the severity of salt-sensitive hypertension. These findings support the interpretation that NRP-C plays an important role in the regulation of NaCl balance and the pathophysiology of salt-sensitive hypertension.
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ACKNOWLEDGEMENTS |
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This work was supported in part by National Heart, Lung, and Blood Institute Grants HL-44195, HL-50147, HL-45990, HL-07457, and HL-56046.
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FOOTNOTES |
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Address for reprint requests and other correspondence: Y.-F. Chen, 1008 Zeigler Research Bldg., Univ. of Alabama at Birmingham, UAB Station, Birmingham, AL 35294 (E-mail: YFChen{at}UAB.EDU).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published August 30, 2001; 10.1152/ajprenal.00166.2001
Received 25 May 2001; accepted in final form 30 August 2001.
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