Institut für 1 Pharmakologie, 3 Anatomie, und 4 Physiologie, der Universität Regensburg, D-93040 Regensburg; and 2 Innere Medizin II, Universitätsklinikum Regensburg, D-93053 Regensburg, Germany
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ABSTRACT |
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We investigated the effect of
cyclooxygenase (COX) activity on the regulation of the
renin-angiotensin-aldosterone system by salt intake. Therefore,
Sprague-Dawley rats were subjected to different salt diets [0.02, 0.6, and 8% NaCl (wt/wt)] and treated with the selective COX-2 inhibitor
rofecoxib (10 mg · kg body wt1 · day
1) or with ketorolac at a
dose selective for COX-1 inhibition (2 mg · kg body
wt
1 · day
1) for 3, 7, 14, and 21 days. Rofecoxib and ketorolac caused a similar reduction of
renocortical PGE2 formation with a low-salt diet. Rofecoxib
did not change plasma renin activity or renocortical renin mRNA
abundance with any of the diets but clearly lowered plasma aldosterone
concentration. In contrast, ketorolac delayed the increase in plasma
renin activity and of renin mRNA in response to low salt intake but did
not change plasma aldosterone concentration. Prolonged treatment with
rofecoxib but not with ketorolac caused an upregulation of COX-2
expression while COX-1 mRNA abundance remained unchanged. These
findings suggest that COX-1-derived, but not COX-2-derived, prostanoids
are of relevance for the regulation of the renin system by salt intake.
cyclooxygenase; kidney
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INTRODUCTION |
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THE ACTIVITY OF THE RENIN-angiotensin-aldosterone system (RAAS) is determined by several factors, including the rate of salt intake (12). It is activated in states of low salt intake and suppressed by high salt intake (1, 32). The regulation of the RAAS by salt intake depends on the regulation of renin synthesis and renin secretion, because the protease renin is regarded as the rate-limiting enzyme of the RAAS. However, the mechanisms linking renin with salt intake have long remained obscure (12). Several studies have shown that the stimulation of the renin system by low salt intake is attenuated by COX inhibitors, suggesting a possible mediator role for prostanoids in the stimulation of the renin system by low salt intake (6, 10). However, COX inhibitors also cause volume retention, particularly in states of sodium depletion (2, 27, 35), and the effect of COX inhibitors on the renin system could therefore be related to volume changes rather than to interference with a direct action of prostanoids in the juxtaglomerular apparatus (29, 31). The demonstration that a low-salt diet enhances the expression of COX-2 in the macula densa cells (15) has reinforced the concept that COX-2-derived prostanoids in the macula densa may directly mediate the effect of salt intake on renin secretion and of renin gene expression in neighboring juxtaglomerular epithelioid cells (7, 24).
Such a concept is in good agreement with the idea of a direct stimulatory effect of PGE2 and PGI2 on juxtaglomerular epithelioid cells (22). It is further supported by reports that selective COX-2 inhibitors attenuate the stimulation of the renin system by low salt intake (13) and that a low-salt diet fails to stimulate the renin system in COX-2-deficient mice (39). At first glance, these data support the concept; however, they are hampered by some peculiarities. Thus administration of preferential COX-2 inhibitors only partially inhibited renin secretion (13, 23). Furthermore, acute intravenous administration of a COX-2 inhibitor had no effect on plasma renin activity (PRA) in rats (13) or dogs (9) kept on a low-salt diet, suggesting that COX-2 inhibition has to last for days to attenuate the stimulation of the renin system by a low-salt diet. Moreover, in COX-2-deficient mice, not only renin expression but also the structure of the kidney is markedly altered (5, 26), suggesting that the altered response of the renin system to low salt intake may not necessarily be linked to the lack of COX-2-generated prostanoids. In fact, there are studies questioning a causal involvement of COX-2-derived prostanoids in the regulation of the renin system by salt intake (18, 23, 31). In view of this unclear situation regarding the role of prostanoids for mediating the influence of salt intake on renin secretion and renin synthesis, it appeared reasonable to us to characterize systematically the involvement of COX-derived prostanoids for the regulation of the RAAS by salt intake. Because different published findings may have resulted from different time protocols of experiments and from different isoform selectivities of the COX inhibitors used, our purpose was to determine time-dependent effects of treatment with three COX inhibitors, including a COX-2-selective inhibitor, a nonselective COX inhibitor, and a preferential COX-1 inhibitor on the RAAS.
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MATERIALS AND METHODS |
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Treatment of animals. Male Sprague-Dawley (SD) rats, 190-210 g, were used for this study (Charles River, Sulzfeld, Germany).
To examine the effect of the COX-2 inhibitor rofecoxib on the modulation of the RAAS by salt intake after a 3-wk treatment, groups of eight rats were treated with either a low-salt diet [0.02% NaCl (wt/wt)], a normal-salt diet [0.6% NaCl (wt/wt)], or a high-salt diet [8% NaCl (wt/wt)] in combination with vehicle or 10 mg · kg body wtSelection of drugs.
Drugs were primarily selected on the basis of the IC80
ratios (whole blood assay-COX-2/COX-1) reported previously
(37). These data suggest that rofecoxib has a
>50-fold COX-2 selectivity, with a low affinity to COX-1, when COX-2
is inhibited by 80%. Meclofenamate is regarded as a dual COX
inhibitor, and ketorolac shows the greatest selectivity for COX-1 of
the nonsteroidal anti-inflammatory drugs on the market. Recently, it
has been shown that the dose of ketorolac used in our study (2 mg · kg body wt1 · day
1)
inhibits COX-1 for >90% without a significant effect on COX-2 activity (36) and that rofecoxib seems to be selective for
COX-2 at the dose used in our study (10 mg · kg body
wt
1 · day
1) (11).
Ribonuclease protection assays for -actin, COX-2, COX-1, and
renin mRNA.
Cytoplasmatic
-actin (1 µg of total RNA) and renocortical COX-1
(100 µg), COX-2 (50 µg), and renin mRNA (50 µg) were determined by specific RNase protection assays, as described previously (25, 38).
Determination of PRA, plasma aldosterone concentration, and renocortical PGE2 concentration. PRA and plasma aldosterone concentration (PAC) were determined with commercially available radioimmunoassays (Sorin Biomedica, Düsseldorf, Germany). Concentration of renal cortical PGE2 was assayed by using a monoclonal enzyme immunoassay kit (Cayman Chemical). One hundred milligrams of renal cortical tissue were homogenized with ice-cold isotonic NaCl solution and centrifuged at 10,000 g for 10 min. A 1:30 dilution of the supernatant was used for the determination of PGE2 and also for the determination of protein according to the method of Lowry.
COX-2 immunoreactivity. COX-2 immunoreactivity was demonstrated as described previously (25). In brief, sections were layered with the primary antibody (dilution 1:500; M19, Santa Cruz Biotechnology, Santa Cruz, CA) and incubated at 4°C overnight. After addition of the second antibody (dilution 1:500; biotin-conjugated, rabbit anti-goat IgG), the sections were incubated with avidin D horseradish peroxidase complex (Vectastain diaminobenzidine kit; Vector Labs) and exposed to 0.1% diaminobenzidine tetrahydrochloride and 0.02% H2O2 as the source of peroxidase substrate. Each slide was counterstained with hematoxylin-eosin. As a negative control, we used the same dilutions of preimmune goat serum (for the primary antibody) or normal rabbit IgG (for the secondary antibody).
Statistical analysis. The data are presented as means ± SE. The level of significance was calculated by ANOVA followed by Student's t-test. A P value <0.05 was considered significant.
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RESULTS |
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Effect of the COX-2 inhibitor rofecoxib on modulation of the RAAS
by salt intake after a 3-wk treatment.
PRA was inversely related to salt intake. Compared with normal salt
intake, PRA increased to ~225% during the low-salt diet and
decreased to ~25% during the high-salt diet. A 3-wk treatment with
rofecoxib (10 mg · kg body
wt1 · day
1) had no influence on PRA
for any of the diets (Fig. 1).
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Time dependency of COX inhibition on the RAAS during low salt intake. In view of the lack of effect of the COX-2 inhibitor on renin secretion and renin gene expression despite significant changes in COX-2 expression and tissue PGE2 concentrations, we considered the temporal pattern of the effects of rofecoxib and compared it with the effects of a preferential inhibition of COX-1 activity. For this purpose, we determined the effects of rofecoxib, the nonselective COX inhibitor meclofenamate, and ketorolac (at a dose selective for COX-1) on the RAAS during low salt intake 3, 7, 14, and 21 days after the start of the treatment.
Renocortical PGE2 concentrations increased with time during low salt intake and reached a plateau of 1.5-fold over the control values after 2 wk of salt restriction (Fig. 3). All three COX inhibitors lowered renocortical PGE2 after 3 days of treatment, which was the first time point examined. The strongest effects were seen with keterolac, which reduced PGE2 by ~60% (Fig. 3). Compared with normal salt intake, PRA increased with time and reached a plateau of about threefold over the control values after 7 days of low salt intake (Fig. 4). Treatment with ketorolac clearly attenuated the increase of PRA at days 7 and 14 but had no inhibitory effect after 3 wk. Similar results were obtained with meclofenamate, which appeared less effective than keterolac. Rofecoxib had no effect on PRA at any time point (Fig. 4).
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Immunohistochemistry for COX-2.
In view of the strong upregulation of COX-2 mRNA by prolonged treatment
with rofecoxib, we were interested in the localization of COX-2 protein
in these kidneys. Figure 8 shows
representative examples of COX-2 immunoreactivity in the kidney of a
control rat during normal salt intake (Fig. 8, A and
B) and low salt intake (Fig. 8, C and
D) and rats kept on a low-salt diet with ketorolac (Fig. 8,
E and F) or rofecoxib (Fig. 8, G and
H) treatment for 3 wk. In the kidneys of control rats, COX-2
immunoreactivity was scarce and was restricted to the cortex, in which
it was mainly associated with juxtaglomerular regions. In
animals on a low-salt diet, COX-2 immunoreactivity increased moderately
without changing the distribution of COX-2 expression. Ketorolac
treatment did not alter the localization of COX-2 protein compared with
low salt intake. In animals on a low-salt diet with additional
rofecoxib treatment, COX-2 immunoreactivity strongly increased but was
still restricted to the cortex. Under this experimental condition, the cortical thick ascending limbs of Henle displayed COX-2
immunoreactivity over almost their entire lengths (Fig. 8,
G and H).
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Time dependency of COX inhibition on systolic blood pressure during
low salt intake.
Systolic blood pressure (sBP) of all animals was ~125-135 mmHg
at the beginning of the treatment and was not altered in control rats
with normal salt intake during the whole treatment period. During low
salt intake, sBP was in the range of 120-130 mmHg and was not
different compared with normal salt intake at all time points
investigated. Low salt intake and rofecoxib treatment did not change
sBP during the 3-wk treatement. In contrast, sBP increased in the range
of 135-145 mmHg in rats subjected to low salt intake and ketorolac
or meclofenamte after 14 days of treatment. However, sBP was not
altered in these animals on days 3 and 7 (Fig.
9).
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Time dependency of COX inhibition on the RAAS during normal salt intake. In view of the attenuation of renin gene expression and renin secretion by ketorolac during low salt intake, we considered the temporal pattern of the effects of rofecoxib and ketorolac on the renin system during normal salt intake. Neither ketorolac nor rofecoxib affected renocortical renin mRNA abundance or PRA at any time point investigated (data not shown). Furthermore, ketorolac did not influence PAC, COX-1, or COX-2 mRNA during normal salt intake, although it decreased basal renocortical PGE2 levels in the range of 40-50% compared with control rats. During normal salt intake, rofecoxib behaved very similarly to what was seen for the low-salt diet. Thus renocortical PGE2 content was decreased to ~50% of the control levels. COX-1 mRNA was not affected, whereas renocortical COX-2 mRNA abundance increased ~1.7-fold over the control values after 14 days of treatment with rofecoxib. PAC was attenuated by rofecoxib after 14 days of treatment in that rofexoxib lowered PAC to ~50% of basal levels.
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DISCUSSION |
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The purpose of our study was to determine the relevance of prostanoids, in particular of COX-2-generated prostanoids, for the regulation of the RAAS by variation of salt intake. In agreement with previous studies (17, 19), we found a time-dependent increase in PRA, PAC, and renin mRNA during low salt intake and an inverse relationship between PRA, PAC, and renin mRNA and the salt content of the diet. Also, COX-2 gene expression in the renal cortex as an indicator for macula densa COX-2 expression (16) changed inversely with the rate of salt intake, thus confirming previous reports (21, 40).
Our data show that renocortical tissue levels of PGE2 are also inversely related to the rate of salt intake and that they can be markedly lowered by preferential COX-1 and COX-2 inhibitors. This finding is compatible with the observation that COX-1 and COX-2 genes are expressed to a similar extent in the renal cortex. With regard to the relevance of PGs for the regulation of renin secretion and renin gene expression by salt intake, our findings would suggest that abolition of COX-1-derived rather than of COX-2-derived prostanoids transiently attenuates the stimulation of the renin system by low salt intake. This conclusion thus supports previous findings obtained with nonselective COX inhibitors (7, 8, 24) and furthermore suggests that macula densa-derived COX-2-mediated prostanoids are not relevant for the regulation of the renin system by salt intake. Several previous studies have suggested that the inhibition by COX inhibitors of renin secretion stimulated by low salt is related to volume retention (29, 31). The finding that COX-1 inhibition only transiently attenuates the stimulation of renin secretion and of renin gene expression indicates that COX-1-derived PGs are not permanently required for the stimulation of the renin system by low salt intake, indicating a more indirect effect of COX-1-derived prostanoids. In summary, we conclude from our findings that PGs are not the direct mediators of salt intake at the level of renal juxtaglomerular cells. This conclusion is in contrast to the concept that mainly COX-2-derived prostanoids should mediate the effect of salt intake on the renin system (14, 39). With regard to the previous observations of our laboratory (23), we found that the attenuation of PRA by COX-2 inhibition during a low-salt diet is a rather inconsistent phenomenon that could not be confirmed in further studies with rats of the Wistar-Kyoto and spontaneously hypertensive strains (Höcherl K, Endemann D, Kammerl MC, Grobecker HF, and Kurtz A, unpublished observations) or with the SD rats in this study.
Nonsteroidal anti-inflammatory drugs are thought to increase blood pressure, which in turn may have a suppressive effect on renin synthesis and renin gene expression, because it is known that blood pressure negatively affects PRA and renin mRNA (12). However, our data do not suggest a major influence of changes in blood pressure on PRA and renocortical renin mRNA abundance during a low-salt diet.
The role of the two COX isoforms in the generation of aldosterone appears to be quite different. It has been suggested that prostanoids are involved in the regulation of aldosterone release at the cellular level (4, 30). Our data would now suggest that mainly COX-2-derived prostanoids are relevant for aldosterone production. A moderate constitutive expression of COX-2 has already been reported for the adrenal cortex (20). From our findings, we conclude that aldosterone regulation by salt intake partially depends on the COX-2 mechanism, but other factors may be involved.
Prolonged administration of COX-2 inhibitors but not of COX-1
inhibitors strongly enhanced COX-2 gene expression in our study. This
enhancement of COX-2 expression occurred in the same structures in
which COX-2 is sporadically found in the kidneys of normal rats,
namely, the cortical thick ascending limbs of Henle, including the
macula densa regions (15, 34). This stimulation of COX-2 expression somewhat resembles the situation of adrenalectomized animals
in which COX-2 expression in the cortical thick ascending limb of Henle
is strongly increased because of mineralocorticoid deficiency
(33). In fact, treatment with the COX-2 inhibitor attenuated aldosterone release. However, whether this lowering of PAC
in conjunction with a low-salt diet is sufficient to cause such strong
stimulation of COX-2 expression remains questionable. Another
explanation could be that COX-2 inhibitors stimulate COX-2 expression
by activating nuclear factor-B, which has been demonstrated in vitro
(28). Finally, a negative feedback of COX-2 expression by
COX-2-derived prostanoids also appears conceivable in principle.
Taken together, our data indicate that in rats, COX-2-derived prostanoids are not essentially required for the regulation of renin secretion, renin synthesis, aldosterone production, and COX-2 expression in the macula densa by salt intake. COX-2-derived prostanoids exert an additional stimulatory effect that amplifies the regulation of aldosterone production by salt intake. Conversely, COX-2-derived prostanoids exert a direct negative effect on COX-2 gene expression.
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ACKNOWLEDGEMENTS |
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The technical assistance provided by Astrid Seefeld, Gertraud Wilberg, and Anna M'Bangui is acknowledged.
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FOOTNOTES |
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This study was supported in part by a grant from the Deutsche Forschungsgemeinschaft (Ku 859/13-1).
Address for reprint requests and other correspondence: K. Höcherl, Institut für Pharmakologie, Universitätsstr. 31, Universität Regensburg, D-93040 Regensburg, 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.
February 26, 2002;10.1152/ajprenal.00347.2001
Received 27 November 2001; accepted in final form 8 February 2002.
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