Departments of 1 Pharmacology, 2 Physiology, and 3 Internal Medicine II, University of Regensburg, 93040 Regensburg, Germany
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ABSTRACT |
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We investigated a possible
involvement of the sympathetic nervous system in the parallel increase
of renin, cyclooxygenase-2 (COX-2), and neuronal nitric oxide synthase
(nNOS) gene expression in the juxtaglomerular apparatus of rat kidneys
induced by salt deficiency. Therefore, we determined the effects of
renal denervation and the -adrenoreceptor antagonist metoprolol (50 mg/kg body wt po, twice a day) on renocortical expression of renin,
COX-2, and nNOS in rats fed a low-salt (0.02% wt/wt) diet or treated for 1 wk with ramipril (10 mg/kg body wt) in combination with a
low-salt diet. We found that a low-salt diet in combination with
ramipril strongly increased renocortical mRNA levels of renin, COX-2,
and nNOS 9-, 7-, and 2.5-fold, respectively. Treatment with metoprolol
did not change basal expression of the three genes or induction of
renin and COX-2 gene expression, while induction of nNOS expression was
clearly attenuated. Similarly, unilateral renal denervation attenuated
induction of nNOS expression but had no effect on all other parameters.
These findings suggest that
-adrenergic stimulation is not required
for stimulation of renin and COX-2 gene expression in the
juxtaglomerular apparatus during salt deficiency. However,
-adrenoreceptor activity or renal nerve activity appears to be
required for the full stimulation of nNOS expression by low salt intake
or combined with angiotensin-converting enzyme inhibition.
cyclooxygenase-2; kidney; renal nerves; neuronal nitric oxide synthase
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INTRODUCTION |
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RECENTLY, IT HAS BEEN
RECOGNIZED that expression of cyclooxygenase (COX)-2 and the
neuronal isoform of nitric oxide synthase (nNOS) changes in renal
macula densa cells in parallel with the expression of renin in the
neighboring juxtaglomerular cells (3-5). Thus low
salt intake (3, 4, 27), fall in renal perfusion pressure (3, 14, 22, 31), and angiotensin II (ANG II) antagonists (6, 19, 33) increase expression of these
genes. Maximum effects have been observed with a low-salt diet in
combination with ANG II antagonists (4, 6, 33). The
pathways triggering the characteristic increase in expression of the
three genes and the physiological implication of the increased
expression are not yet clear. It has been suggested that the increase
in renin expression may be causally related to a preceding increase in formation of COX-2-derived prostanoids in macula densa cells (1, 10, 18, 20). The increase in COX-2 expression in the macula densa, in turn, has been suggested to be dependent on nNOS activity in
the macula densa (5), leading to the concept of a
sequential stimulation: nNOS COX-2
renin. This concept,
however, is questioned by other findings, which could not confirm a
role for COX-2-derived prostanoids in expression of renin
(22, 23) or confirm a functional interdependence of nNOS
and COX-2 in macula densa cells (4). Therefore, we
considered alternative pathways that could be relevant for the
concerted induction of renin, COX-2, and nNOS in states of salt
deficiency. We focused our interest on the sympathetic nervous system,
which could be a mediator candidate, because the sympathetic nervous
system will be activated by volume depletion and/or a fall in blood
pressure during salt deficiency (8, 16, 29, 30) and
because renin-producing juxtaglomerular cells (2, 15) and
macula densa cells (2, 15) are equipped with
-adrenoreceptor. Therefore, it appeared reasonable to determine the
relevance of sympathetic outflow for stimulation of renin, COX-2, and
nNOS gene expression by salt depletion. For this purpose, we performed
experiments with
-adrenoreceptor blockade and with unilateral renal
denervation of rats fed a low-salt diet alone or in combination with
treatment with an angiotensin-converting enzyme (ACE) inhibitor. A
low-salt diet alone is known to induce only a minor stimulation of
renin, COX-2, and nNOS gene expression (4, 12, 13, 28),
whereas additional treatment with an ACE inhibitor strongly increases
these three genes in the rat renal cortex (4, 28).
Although the model of a low-salt diet in combination with ACE
inhibition may have some limitations (stimulation of the renal
baroreceptor, alterations in renal blood flow and glomerular filtration
rate, interruption of the angiotensin-mediated negative-feedback
pathway on renin), a possible effect of
-adrenoreceptor blockade on
induction of these genes may become more apparent in this experimental
setting because of the strong stimulation of renin, COX-2, and nNOS
gene expression.
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METHODS |
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Male Sprague-Dawley rats (150-180 g; Charles River, Sulzfeld, Germany) were habituated for 5 days and had access to tap water ad libitum. Body weight and systolic blood pressure (tail cuff method) were monitored daily.
Rats were divided into 9 groups of 10 rats each and treated for 1 wk as
follows: 1) normal diet [0.6% (wt/wt) NaCl; Altromin, Lage, Germany] and vehicle; 2) normal diet and metoprolol
tartrate (50 mg/kg twice a day); 3) low-salt diet [0.02%
(wt/wt) NaCl; Ssniff Special Diets, Soest, Germany] and vehicle;
4) low-salt diet and metoprolol tartrate (50 mg/kg twice a
day); 5) low-salt diet and ramipril (10 mg · kg1 · day
1) in
drinking water; 6) low-salt diet and ramipril (10 mg · kg
1 · day
1) in
drinking water and metoprolol tartrate (50 mg/kg twice a day);
7) left-side renal denervation by a combination of
mechanical and chemical methods, as described previously
(16), and, after 3 days, a normal-salt diet for 1 wk;
8) left-side renal denervation followed by a low-salt diet;
and 9) left-side renal denervation followed by a low-salt
diet in combination with ramipril (10 mg · kg
1 · day
1) in
drinking water.
Rats were killed by decapitation during anesthesia with sevoflurane. Ramipril and metoprolol were gifts from AstraZeneca (Mölndal, Sweden).
Samples.
Blood was collected into EDTA tubes. The kidneys were quickly removed
and cut into longitudinal halves. Cortexes were dissected with a
scalpel blade under a stereomicroscope, frozen in liquid nitrogen, and
stored at 80°C until extraction of total RNA (7).
Ribonuclease protection assays for -actin, renin, COX-1,
COX-2, nNOS, and endothelial NOS.
-Actin, renin, COX-1, COX-2, nNOS, and endothelial NOS (eNOS) mRNA
levels were measured by ribonuclease protection assays, as described
elsewhere (4, 26). Briefly, cRNA probes (5 × 105 cpm) were hybridized at 60°C overnight with 40 µg
of total RNA for COX-1 and COX-2, 100 µg of total RNA for nNOS and
eNOS, 20 µg of total RNA for renin, 1 µg of total RNA for
-actin, and 20 µg of total RNA for negative control. Then they
were digested with ribonuclease A/T1 (room temperature for
30 min) and proteinase K (37°C for 30 min). After phenol-chloroform
extraction and ethanol precipitation, protected fragments were
separated on an 8% polyacrylamide gel. The gel was dried for 2 h,
and bands were quantitated by phosphorimaging (Instant Imager 2024, Packard). Autoradiography was performed at
80°C for 1-3 days.
Figure 1 shows typical autoradiographs of
gels using renocortical total RNA (20 µg of total RNA for renin mRNA,
40 µg for COX-2, and 100 µg for nNOS) of six rats: two fed a
normal-salt diet, two treated with ramipril and fed a low-salt diet,
and two treated with ramipril and metoprolol and fed a low-salt diet.
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Immunoblotting for nNOS, eNOS, and COX-2 protein in the rat renal cortex. One hundred micrograms of total renocortical protein were loaded per lane, separated by an 8% SDS-polyacrylamide gel (10% for COX-2), and transferred onto a nitrocellulose membrane (Bio-Rad). Membranes were blocked overnight at 4°C and incubated with the following antibodies for 2 h at room temperature: nNOS (diluted 1:500; Transduction Laboratories), eNOS (diluted 1:500; Transduction Laboratories), COX-2 (diluted 1:500; Santa Cruz), and a horseradish peroxidase-labeled secondary antibody (goat anti-mouse IgG, diluted 1:500). Detection was achieved by enhanced chemiluminescence (Amersham). The band intensities were quantified by densitometry.
Determination of tissue catecholamines. Catecholamines were determined by reverse-phase high-performance liquid chromatography (HPLC) with electrochemical detection, as previously described in detail (9). Renal cortex samples were frozen in liquid nitrogen and pulverized with a mortar. Catecholamines were extracted from 200-mg tissue samples in 10 volumes of 0.2 M perchloric acid (wt/vol) containing 3,4-dihydroxybenzylamine as internal standard and further treated as described elsewhere (9).
Determination of plasma renin activity. Plasma renin activity (PRA) was determined using an commercially available radioimmunoassay kit (Sorin Biomedica, Düsseldorf, Germany).
Statistical analysis. Values are means ± SE. Levels of significance were calculated by ANOVA followed by Bonferroni's test for multiple comparisons. P < 0.05 was considered statistically significant.
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RESULTS |
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Systolic blood pressure and heart rate.
Systolic blood pressure was 120-130 mmHg for control rats fed a
normal-salt diet and 115-125 mmHg for rats fed a low-salt diet.
Treatment with metoprolol did not change systolic blood pressure.
Ramipril in combination with a low-salt diet lowered systolic blood
pressure significantly to 90-100 mmHg. Additional treatment with
metoprolol did not further decrease systolic blood pressure (Fig.
2).
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PRA and renin mRNA.
A low-salt diet alone increased PRA and renocortical renin mRNA
abundance about twofold. The combination of a low-salt diet and ACE
inhibitor strongly increased PRA about eightfold and renal renin mRNA
abundance about ninefold. Metoprolol did not change basal PRA or renin
mRNA. Moreover, metoprolol attenuated the rise of PRA and renin mRNA in
response to a low-salt diet only marginally. Furthermore, metoprolol
did not change the rise of PRA and renin mRNA in response to salt
depletion and ramipril (Fig. 3).
Left-side renal denervation did not affect PRA during basal conditions
or during low salt intake or low salt intake and ramipril treatment. Denervation significantly lowered basal expression of renin mRNA, but
the increase during low salt intake or during salt depletion and
ramipril treatment was not attenuated (Fig. 3).
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Renocortical COX-2 and COX-1 mRNA.
A low-salt diet alone increased renocortical COX-2 mRNA abundance about
twofold, whereas additional treatment with ramipril strongly increased
COX-2 mRNA about sevenfold. Metoprolol did not change basal COX-2 mRNA.
Moreover, metoprolol did not attenuate the rise of COX-2 mRNA in
response to a low-salt diet or low salt intake and ramipril (Fig.
4). Left-side renal denervation did not
change COX-2 mRNA during basal conditions or during salt depletion achieved by low salt intake or low salt intake and ramipril
treatment (Fig. 4).
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Renocortical nNOS and eNOS mRNA.
A moderate increase of ~1.7-fold for nNOS mRNA was observed during
low salt intake. A low-salt diet in combination with ACE inhibitor
treatment increased nNOS mRNA ~2.5-fold. Metoprolol did not change
basal nNOS mRNA abundance but clearly attenuated the rise of nNOS mRNA
in rats fed a low-salt diet and in rats fed a low-salt diet and treated
with ramipril (Fig. 5). Left-side renal
denervation did not change nNOS mRNA during basal conditions but
attenuated nNOS mRNA during low salt intake and low salt intake combined with ACE inhibition.
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Effect of salt depletion on renal cortical catecholamine
concentration.
Norepinephrine and dopamine concentrations remained unchanged during
low salt intake and low salt intake in combination with ramipril
treatment. Epinephrine content was at the limit of determination (Table
1). Metoprolol treatment had no influence
on catecholamine concentration in any of the experimental maneuvers
(data not shown). Catecholamine content of innervated kidneys from
untreated and treated rats showed no difference compared with
kidneys from vehicle-treated rats, rats fed a low-salt diet, or
rats treated with ramipril and fed a low-salt diet. In the denervated
kidneys of rats fed a low-salt diet or rats treated with ramipril and
fed a low-salt diet, norepinephrine content dropped to ~4% of that
in the contralateral innervated kidneys. Similarly, also dopamine
concentrations in the denervated kidneys fell to ~35% of that in
innervated kidneys. These results did not differ from untreated rats
(Table 1).
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Renocortical nNOS, eNOS, and COX-2 protein expression.
Renocortical immunoreactivity for COX-2 showed a significant threefold
increase in rats fed a low-salt diet and treated with ramipril compared
with vehicle-treated rats, whereas additional feeding with metoprolol
had no further influence (Fig. 6,
top). Renocortical immunoreactivity for nNOS showed a
1.8-fold significant increase in rats fed a low-salt diet and treated
with ramipril compared with vehicle-treated rats. Additional feeding
with metoprolol clearly attenuated the rise of nNOS protein in response
to a low-salt diet and ramipril treatment (Fig. 6, middle).
eNOS immunoreactivity was not changed during any of these experimental
maneuvers (Fig. 6, bottom).
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DISCUSSION |
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Our study aimed to assess the relevance of renal nerve activity
and the involvement of -adrenoreceptor activity in the well-known upregulation of renin, COX-2, and nNOS gene expression in the juxtaglomerular apparatus during low salt intake and low salt intake in
combination with ACE inhibition. In confirmation of previous data, we
found that a low-salt diet moderately upregulated renin, COX-2, and
nNOS mRNAs and proteins and that a low-salt diet in combination
with blockade of the renin-angiotensin system by ACE inhibition
strongly upregulated renin, COX-2, and nNOS mRNAs and proteins in the
kidney cortex (4). Because renin, COX-2, and nNOS mRNA
levels in the cortex correlate well with the expression of the
respective encoded proteins in juxtaglomerular cells (renin)
(14) and macula densa cells (COX-2 and nNOS) (14, 32, 33), we considered the mRNA abundance to be a quantifiable measure for expression of these genes in the juxtaglomerular apparatus. Our findings now show that salt depletion plus ramipril treatment lowered blood pressure and increased heart rate, suggesting sympathetic activation of the cardiovascular system. This assumption is supported by the finding that inhibition of
-adrenoreceptors lowered heart rate of the hypotensive animals into the normal range. Renocortical catecholamines, however, showed only minor changes. Nonetheless, the
increase of nNOS induced by the combination of low salt intake and ACE
inhibition was markedly attenuated by
-adrenoreceptor blockade as
well as the more moderate increase induced by low salt intake alone.
Expression of the renin gene was only marginally affected by
-adrenoreceptor blockade, while COX-2 mRNA and protein were not
attenuated. Data similar to those obtained with
-adrenoreceptor blockade were obtained with renal denervation, suggesting that it is
likely that renal nerves influence expression of juxtaglomerular genes
via
-adrenoreceptors. A possible effect of
-adrenoreceptor activation on gene expression in renal juxtaglomerular epithelioid cells and macula densa cells is in good accordance with the existence of
1- and
2-adrenoreceptors on the
surface of these cells (2, 15). Intracellular signaling of
-adrenoreceptors through the cAMP pathway (11) would
suggest that cAMP influences expression of the nNOS. Such an effect of
cAMP coincides with the observation that cAMP/Ca2+ is a
possible inducer of nNOS gene expression in primary embryonic cortical
neurons (25). Notably, COX-2 gene expression and protein level were not affected by
-adrenoreceptor blockade, suggesting that
cAMP is of minor relevance for the expression of COX-2 gene and protein
in the macula densa. Moreover, the different behavior of nNOS and COX-2
expression does not support the concept that COX-2 expression is
secondary to nNOS expression (5).
Renin gene expression.
The cAMP pathway is the best-established stimulatory pathway for renin
secretion and renin gene expression (19), and renal nerve
activity has been found to be important not only for basal expression
of renin (16), but also for stimulation of renin secretion
and renin gene expression in response to a fall of renal perfusion
pressure (29). However, in this context, the effects of
-adrenoreceptor blockade and renal denervation on the strong stimulation of renin secretion and renin gene expression by the combination of low salt intake and ACE inhibition and also on stimulation by low salt intake were rather marginal, indicating that
renal nerve activity plays only a minor role in stimulation of the
renin system during salt depletion (8). It is well known that ACE inhibitors and ANG II type 1 receptor antagonists markedly stimulate renin secretion and renin gene expression (6,
33), but to a much lower extent than the combination of ACE
inhibition and low salt intake (4, 33). Because low salt
intake per se stimulates renin gene expression only moderately
(4, 33), stimulation of the renin system by a low-salt
diet in combination with ACE inhibition is therefore clearly
overadditive relative to the individual effects of ACE inhibition and a
low-salt diet. It is conceivable that stimulation of the renin system
by a low-salt diet is already limited by ANG II negative-feedback
inhibition. Interruption of this feedback mechanism by ACE inhibition
during low salt intake will therefore strongly enhance stimulation of the renin system to an extent seen in this and previous studies (4, 33). Such a disinhibition of the renin system by ACE inhibition raises the question about the factors causing the
"background" stimulation of the renin system under basal conditions
and, in particular, during low salt intake. Apparently, renal nerve
activity is not essentially required as a stimulatory signal in this
context. Therefore, identification of the underlying mechanisms remains a task for future work.
COX-2 gene expression. COX-2 gene expression in the cortical thick ascending limb of Henle, including the macula densa region, shows a striking parallelism to expression of renin in the neighboring juxtaglomerular epithelioid cells (6, 14, 22, 33), which has led to the concept that expression of renin is essentially regulated by macula densa-derived prostanoids triggered by the expression of COX-2 (5, 6, 31). Because this intriguing concept is still a matter of controversy (4, 21-24), it appears not unlikely that renin and COX-2 gene expression could alternatively be regulated in parallel by a common yet unknown denominator. If this is the case, strong stimulation of COX-2 expression by the combination of low salt intake and an ACE inhibitor may reflect the interruption of a negative control of COX-2 expression by ANG II, as assumed for stimulation of the renin system. The existence of ANG II type 1 receptors on the surface of macula densa cells would be compatible with such an idea. Again the identity of the background stimulator of COX-2 in the macula densa remains an open question.
nNOS gene expression. nNOS expression in the macula densa appears to be regulated by pathways that are somewhat different from those that regulate renin and COX-2. Such a difference is already suggested by the smaller amplitude of stimulation than that caused by renin and COX-2 and is confirmed by the dependency on renal nerve activity.
Neither renal activity nor catecholamines appear to be of major relevance for stimulation of renin and COX-2 expression in the juxtaglomerular apparatus during low salt intake or low salt intake in combination with ACE inhibition. Renal nerve activity, however, appears to be required for full stimulation of nNOS expression in the macula densa in this situation, an effect being mediated by ![]() |
ACKNOWLEDGEMENTS |
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The expert technical assistance of A. Seefeld, G. Wilberg, M. Hamann, and K.-H. Götz is gratefully acknowledged.
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FOOTNOTES |
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This study was supported in part by Deutsche Forschungsgemeinschaft Grant Ku 859/13-2.
Address for reprint requests and other correspondence: K. Höcherl, Institut für Pharmakologie der Universität Regensburg, Universitätsstr. 31, Regensburg 93040, Germany (E-mail: klaus.hoecherl{at}chemie.uni-regensburg.de).
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.
10.1152/ajprenal.00209.2001
Received 5 May 2001; accepted in final form 2 October 2001.
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