1 Institut für Physiologie and 2 Klinik und Poliklinik für Innere Medizin, Universität Regensburg, 93040 Regensburg, Germany; and 3 National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892
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ABSTRACT |
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Recent studies demonstrated that
the influence of the macula densa on glomerular filtration is abolished
in adenosine A1 receptor (A1AR) knockout mice.
Inasmuch as the macula densa not only regulates glomerular filtration
but also controls the activity of the renin system, the present study
aimed to determine the role of the A1AR in macula densa
control of renin synthesis and secretion. Although a high-salt diet
over 1 wk suppressed renin mRNA expression and renal renin content to
similar degrees in A1AR+/+,
A1AR+/, and A1AR
/
mice, stimulation of Ren-1 mRNA expression and renal renin
content by salt restriction was markedly enhanced in
A1AR
/
compared with wild-type mice.
Pharmacological blockade of macula densa salt transport with loop
diuretics stimulated renin expression in vivo (treatment with
furosemide at 1.2 mg/day for 6 days) and renin secretion in
isolated perfused mouse kidneys (treatment with 100 µM bumetanide) in
all three genotypes to the same extent. Taken together, our data are
consistent with the concept of a tonic inhibitory role of the
A1AR in the renin system, whereas they indicate
that the A1AR is not indispensable in macula
densa control of the renin system.
loop diuretics; low salt; high salt
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INTRODUCTION |
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THE KIDNEYS PLAY A KEY ROLE in maintenance of fluid and electrolyte balance of the body as well as in blood pressure regulation. Multiple extra- and intrarenal factors cooperate in the adjustments of renal function that underlie body fluid homeostasis. A specific intrarenal control element for NaCl excretion is the juxtaglomerular apparatus, the anatomic substrate of a mechanism in which changes in tubular salt delivery are sensed and translated to changes in afferent arteriolar tone [tubuloglomerular feedback (TGF)] and renin synthesis and secretion (macula densa-mediated renin release). An increase in NaCl concentration at the macula densa results in vasoconstriction of the afferent arteriole, reducing glomerular filtration rate and tubular salt load, and inhibition of the renin-angiotensin system; a decrease in macula densa NaCl concentration has the opposite effect. The nature of the extracellular signaling events between macula densa cells and vascular smooth muscle or renin-producing effector cells is still a matter of debate. Besides cyclooxygenase-2-derived prostanoids (3, 9, 10, 12, 16, 31), the nucleoside adenosine has been proposed to be centrally involved in macula densa control of the renin system and glomerular filtration, inasmuch as adenosine is an inhibitor of the renin system as well as a vasoconstrictor of the afferent arteriole (13, 14), both effects being mediated by the A1 adenosine receptor (A1AR). The inhibitory effect of the A1AR on the renin system has been demonstrated in vitro and in vivo, inasmuch as selective A1AR agonists suppress renin secretion and pharmacological blockade of the A1AR results in stimulation of renin secretion (1, 5, 6, 17, 24). The putative role of adenosine in the salt-dependent regulation of the renin system is underlined by several studies suggesting a relationship between tubular salt load and adenosine concentration in the kidney. Infusion of hypertonic saline or a high dietary sodium intake, both of which are associated with an inhibition of the renin system, led to elevated adenosine concentrations in the kidney (23, 27, 37). In contrast, dietary sodium restriction, known to stimulate the renin system, resulted in reduced renal interstitial concentrations of adenosine (27). Therefore, an increase in adenosine concentrations due to a high tubular salt load could mediate vasoconstriction and inhibition of the renin system, whereas a decrease in renal adenosine concentration resulting from a reduced salt load could cause vasodilatation and stimulation of the renin system. The A1AR agonist cyclohexyladenosine (CHA) suppressed stimulation of renin secretion in response to a perfusion medium containing a low NaCl concentration in the isolated juxtamedullary apparatus, and blockade of the A1AR diminished the reduction in renin secretion caused by high luminal NaCl concentrations (35), supporting the involvement of adenosine in macula densa control of the renin system. However, in a similar experimental setup, application of exogenous adenosine did not fully mimic the inhibitory effects of increasing tubular NaCl concentration on renin secretion (19), which would be expected from a mediator of macula densa control of the renin system.
Recent investigations have provided direct evidence that adenosine is required for the vasoconstriction caused by TGF. Consistent with earlier studies showing that inhibition of adenosine production (29) or selective blockade of the A1AR (26, 36) blunts TGF, mice with a genetic deletion of the A1AR lack the TGF response to an increase in tubular NaCl concentration (2, 28). Inasmuch as the effector cells of the TGF, namely, the vascular smooth muscle cells of the afferent arteriole, are located in the immediate vicinity of the renin-producing juxtaglomerular cells, it is reasonable to assume that adenosine mediating the TGF also influences the renin system. Therefore, the present experiments were performed to determine whether adenosine and A1AR may be centrally involved in macula densa control of the renin system. Utilizing A1AR knockout mice, we determined whether the absence of the A1AR is associated with altered expression or secretion of renin consistent with tonic inhibition of the renin-angiotensin system by adenosine. Furthermore, the macula densa mechanism is believed to be critically involved in adjustment of the renin system to different salt loads of the body, with a high sodium intake inhibiting and a low sodium intake stimulating the renin system (8, 18, 25, 33). Pharmacological blockade of macula densa NaCl transport with loop diuretics is an intervention that, similar to a low-salt diet, stimulates the renin-angiotensin system by diminishing the NaCl transport-dependent, renin-inhibitory signal to the granular cells (11). Therefore, we investigated the influence of a high- and a low-salt diet and furosemide on the renin system in mice with a genetic deletion of the A1AR. Finally, to assess the more acute modulation of renin secretion by the macula densa, we investigated the effects of the loop diuretic bumetanide on the rate of renin secretion in isolated perfused kidneys of A1AR knockout mice and their wild-type controls. The isolated perfused kidney model is ideally suited to investigate renin secretion in the absence of interindividual differences in systemic factors that may influence the renin system, such as variations in blood pressure or renal sympathetic nerve activity, for example.
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MATERIALS AND METHODS |
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A1AR knockout mice. A1AR knockout mice were generated as described by Sun et al. (28). The mice were derived from two heterozygous breeder pairs. For genotyping, tail biopsies were performed, and DNA was extracted and tested for the presence of wild-type and mutant genes using A1AR- and Neo-R-specific PCR primers (28).
Experimental procedures in vivo.
In the first set of experiments, 10 mice of each genotype
(A1AR+/+, A1AR+/, and
A1AR
/
, 20-24 g body wt) were fed a
low-salt (0.02% NaCl) or a high-salt (8% NaCl) diet for 7 days. As
controls, 10 mice of each genotype were fed normal mouse chow (0.6% NaCl).
Determination of preprorenin mRNA and cytosolic -actin by
RNase protection assay.
After isolation of total RNA from the frozen kidney using the method of
Chomczynski and Sacchi (4), renin was measured by an RNase
protection assay using an antisense RNA probe suitable for detecting
mRNA levels from the Ren-1 and Ren-2 genes as
described previously (32). Cytosolic
-actin was
measured by an RNase protection assay as described elsewhere
(32). For semiquantification of Ren-1 and
Ren-2 mRNA abundance, the hybridization signals were related
to those obtained for
-actin mRNA.
-Actin mRNA levels were not
different between the different genotypes and the different experimental maneuvers (not shown).
Determination of renal renin content.
The renal renin content was determined by measuring the capacity of
homogenized kidneys to generate angiotensin I according to a
modification of the method described by Norling et al.
(22). Frozen kidneys were halved, homogenized in 1 ml of
homogenization buffer [5% (vol/vol) glycerol, 0.1 mM
phenylmethylsulfonyl fluoride, 10 mM EDTA, and 0.1 mM
4-(2-aminomethyl)benzenesulfonyl fluoride] for 30 s
(Ultra-Turrax, IKA Labortechnik), and centrifuged at 4°C at 14,000 g for 5 min. The supernatants were frozen at 20°C and
then thawed three times by alternating the temperature between
20°C
and 4°C. Supernatants were incubated with saturating concentrations of rat renin substrate, and the generated angiotensin I was assayed with a commercial radioimmunoassay kit (Byk and DiaSorin).
Isolated perfused mouse kidney.
Male A1AR/
,
A1AR+/
, and A1AR+/+
mice (20-23 g body wt) with free access to commercial pellet chow
and tap water were used as kidney donors. The animals were anesthetized
with an intraperitoneal injection of
5-ethyl-5-(1-methylbutyl)-2-thiobarbituric acid (100 mg/kg; Trapanal,
Byk Gulden) and ketamine HCl (80 mg/kg; Curamed, Germany) and placed on
a heating table. The abdominal cavity was opened by a midline incision,
and the aorta was clamped distal to the right renal artery so that the
perfusion of the right kidney was not disturbed during the subsequent
insertion of the perfusion cannula into the abdominal aorta distal to
the clamp. The mesenteric artery was ligated, and a metal perfusion
cannula (0.8 mm OD) was inserted into the abdominal aorta. After
removal of the aortic clamp, the cannula was advanced to the origin of
the right renal artery and fixed in this position. The aorta was
ligated proximal to the right renal artery, and perfusion was started
in situ with an initial flow rate of 1 ml/min. With the use of this
technique, a significant ischemic period of the right kidney
was avoided. Finally, the right kidney was excised, placed in a
thermostated moistening chamber, and perfused at constant pressure (100 mmHg). Perfusion pressure was monitored within the perfusion cannula (Isotec pressure transducer, Hugo Sachs Elektronik), and the pressure signal was used for feedback control (model SCP 704, Hugo Sachs Elektronik) of a peristaltic pump. Finally, the renal vein was cannulated (1.5-mm-OD polypropylene catheter). The venous effluent was
drained outside the moistening chamber and collected for determination of renin activity and venous blood flow.
Statistical analysis. Values are means ± SE. Differences between groups were analyzed by ANOVA and Bonferroni's adjustment for multiple comparisons. In the isolated perfused kidney experiments, all values obtained within an experimental period (n = 4) were averaged and compared with the average values of an adjoining experimental period. Student's paired t-test was used to calculate levels of significance within individual kidneys. P < 0.05 was considered statistically significant.
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RESULTS |
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Serum concentrations of sodium, chloride, or potassium were not different between any of the genotypes or the treatment groups (not shown).
Basal renin expression.
Basal renal renin content was 1.5-fold higher in
A1AR/
than in wild-type mice (Fig.
1A).
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Effect of a high-salt diet on renin expression.
A high-salt diet for 1 wk resulted in inhibition of Ren-1
mRNA expression irrespective of the genotype (0.6-, 0.54-, and
0.66-fold of control for A1AR/
,
A1AR+/
, and A1AR+/+,
respectively, all P < 0.05; Fig. 2A).
Moreover, Ren-2 mRNA levels were suppressed by the high-salt
diet in the kidneys of A1AR
/
and
A1AR+/
mice, whereas no Ren-2 mRNA
signal was detectable in the kidneys of A1AR+/+
mice (Fig. 2B). According to the changes in Ren-1
and Ren-2 gene expression, total renin mRNA expression was
significantly suppressed by a high-salt diet in all three genotypes
(Fig. 2C). In parallel with the changes in renin gene
expression, renal renin content was lowered to ~0.6-fold of control
by a low-salt diet in A1AR
/
,
A1AR+/
, and A1AR+/+
mice (P < 0.05; Fig.
3A).
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Effect of a low-salt diet on renin expression.
Dietary salt restriction stimulated the renin system in all three
groups of animals. However, in contrast to the changes due to a
high-salt diet, there were marked differences between the genotypes:
stimulation was most pronounced in A1AR/
mice, in which Ren-1 mRNA levels increased 2.5-fold compared with control animals fed a normal-salt diet, whereas in
A1AR+/+ mice only a 1.2-fold increase was
detected. A1AR+/
mice showed an intermediate
stimulation of renin mRNA, with Ren-1 mRNA levels showing a
twofold upregulation (Fig. 2A).
Effect of furosemide on renin expression.
Blockade of thick ascending limb and macula densa salt transport with
furosemide administration for 6 days stimulated Ren-1 expression in A1AR/
,
A1AR+/
, and
A1AR+/+ mice to similar degrees, so
that no differences in Ren-1 expression exist between
genotypes (Fig. 4). Again,
Ren-2 mRNA was not detectable in
A1AR+/+ mice, whereas it was significantly
stimulated in A1AR
/
and
A1AR+/
mice (Fig. 4). Total renin mRNA
expression was stimulated by furosemide in all groups, with the highest
abundance detectable in the A1AR
/
mice.
Furosemide also augmented renal renin content in all three groups of
mice to a similar extent, so that no significant differences were
detected between the different genotypes (Fig. 3C).
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Effect of bumetanide administration on renin secretion in isolated
perfused mouse kidneys.
To investigate the acute effects of loop diuretics on renin secretion,
we adapted the model of the isolated perfused rat kidney to the
anatomic conditions of mice. This model allows us to study the acute
regulation of renin secretion without interference by confounding
systemic side effects of the experimental drug or systemic
counterregulations. Basal renin secretion rates of isolated perfused
kidneys were similar in A1AR/
,
A1AR+/
, and A1AR+/+
mice (Fig. 5). Blockade of thick
ascending limb and macula densa salt transport by bumetanide resulted
in significant and comparable increases in renin secretion in
A1AR+/+, A1AR+/
, and
A1AR
/
mice: 3.1-, 3.0-, and 2.8-fold of
control, respectively. During subsequent administration of the
A1AR agonist CHA, renin secretion rates returned to basal
levels in kidneys of A1AR+/+ and
A1AR+/
mice, whereas CHA was without effect
in A1AR
/
mice (Fig. 5).
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DISCUSSION |
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The present experiments in A1AR knockout mice aimed to
assess the chronic role of A1AR in the renal expression of
renin under basal conditions as well as in the macula densa control of
the renin system. Previous pharmacological studies provided evidence for a direct inhibitory role of adenosine on renin expression and renin
secretion, an effect that appeared to be mediated by A1AR
(1, 5, 15, 17, 24, 35). The present observation that renal
renin content under basal conditions is elevated in A1AR
knockout mice supports the concept of a tonic inhibition of the
renin-angiotensin system through A1AR mediation. However, besides the direct disinhibition of the renin system by
A1AR deletion, an enhanced sodium excretion reported
previously in A1AR/
mice (2)
as well as after acute pharmacological blockade of A1AR
(36) might also account, in part, for the higher renin content in A1AR
/
mice. The finding that
A1AR
/
mice possess two renin genes
(Ren-1d and Ren-2), whereas wild-type
mice harbor only one renin gene (Ren-1c), and
that this discrepancy is related, as discussed in detail below, to the
different mouse strains used in the generation of the knockout mice
somewhat complicates the straightforward interpretation of our data.
Inasmuch as, in general, plasma renin activities and concentrations
appear to be markedly higher in two-renin than in one-renin gene
strains (20, 34), it is conceivable that the higher renin
content in the A1AR
/
animals is the
consequence of their expression of Ren-1d and
Ren-2. However, the differences in Ren-2
expression do not explain the marked enhancement of Ren-1
mRNA stimulation in A1AR
/
animals by a
low-salt diet, so this result further supports the concept of a tonic
inhibitory role of A1AR in the renin system.
The main intention of our study was to clarify the specific role of
A1AR in the macula densa control of the renin system. The
rationale for the assumption of a central role of the A1AR in this process was as follows: 1) adenosine inhibits the
renin system via the A1AR, 2) adenosine
concentration in the kidney changes in parallel with the sodium load of
the kidney, and 3) A1AR is essentially required
for control of glomerular filtration by the macula densa. According to
the hypothesis that the macula densa-controlled changes in renin
expression and secretion are related to salt-dependent changes in the
intrarenal adenosine concentration, the amplitude of the inhibition of
the renin system due to a high-salt diet or the stimulation due to a
low-salt diet should be attenuated or even blunted in mice lacking the
A1AR. However, our results demonstrate that a high-salt
diet suppressed renal renin mRNA expression and renal renin content to
the same extent in A1AR/
and
A1AR+/+ mice, clearly arguing against a role of
the A1AR in mediation of this process. Moreover,
stimulation of the renin system by a low-salt diet was not diminished,
but was even enhanced, by the genetic deletion of the A1AR,
a further result that is not compatible with a role of A1AR
in mediation of this stimulation. If stimulation of renal renin content
and mRNA expression by the low-salt diet were related to the known
decrease in renal adenosine concentration and the subsequent
disinhibition of the A1AR, this should not be possible in
mice lacking this receptor. However, as stated above, the pronounced
stimulation of Ren-1 mRNA expression due to salt restriction
is highly consistent with a tonically inhibitory role of the
A1AR on the renin system, which is absent in
A1AR
/
mice. The conclusion that the
A1AR is not causally involved in regulation of the renin
system by the macula densa is further supported by the intact
stimulation of the renin gene expression and renin content by blockade
of the macula densa salt transport with furosemide in
A1AR
/
animals. Interpretation of the in
vivo data is limited by the fact that salt restriction or furosemide
treatment might affect renin expression through pathways independent
from or in addition to the macula densa mechanism, for example, by
alterations in blood pressure or in sympathetic nervous system
activity. We therefore investigated the effects of loop diuretics on
renin secretion in the isolated perfused kidney model. In this
preparation, administration of loop diuretics would appear to act
solely through the macula densa, because perfusion pressure is
experimentally controlled and changes in sympathetic nerve activity are
unlikely. Even under these experimental conditions, bumetanide
stimulated renin secretion to the same extent in kidneys of
A1AR
/
mice and their wild-type controls,
arguing against a role of this receptor in mediation of this process.
However, the complete reversal of the stimulated renin secretion by the
selective A1AR agonist CHA in
A1AR+/+ and A1AR+/
mice underlines the direct suppressive effects of the A1AR
on renin secretion, as has been demonstrated in previous studies (1, 5, 6, 15, 19). Besides the advantages of constant experimental conditions, the isolated perfused mouse kidney model is
suitable for use in investigating the acute effects of an inhibition of
macula densa salt transport on renin secretion and, therefore, in
examining the renin system in a time frame similar to that used in the
studies demonstrating the absence of a TGF response in
A1AR
/
mice (2, 28). Because
the TGF response has been found to be abolished by pharmacological
blockade or genetic deletion of the A1AR (2, 26, 28,
29, 36), regulation of glomerular filtration rate and control of
the renin system by the macula densa appear to follow different pathways.
A further interesting result of our study is the discovery of a linkage
between the A1AR mutation and the renin gene locus that
causes homozygosity in the A1AR knockout genotype to be
invariably associated with the two-renin gene constellation. In
contrast, the wild-type phenotype, homozygous for the absence of the
A1AR mutation, always contains a single renin gene. The
foundation for this linkage is the fact that the genes encoding the
A1AR and renin are localized on chromosome 1 in close
vicinity, as first shown in humans (7, 30). Analysis
of available mouse genomic sequences has confirmed that the renin and
A1AR genes in the mouse are also located on chromosome 1 in
relative close juxtaposition, separated by ~850 kb of DNA containing
several putative gene loci. As is commonly done, the embryonic stem
cells used for targeted disruption of the A1AR gene were
derived from the 129J mouse strain, one of several mouse strains with
two renin genes, designated Ren-1d and
Ren-2 (21). By propagating the A1AR
mutation in the one-renin gene C57BL/6 background,
A1AR/
mice will carry the 129J background
in the area of the mutated A1AR gene and will therefore
possess two renin genes. On the other hand,
A1AR+/+ mice will have to carry the C57BL/6
background in the area of the native A1AR gene and will
therefore have only one renin gene, designated
Ren-1c. Breeding strategies will be used to
segregate the A1AR knockout mutation from the two-renin
gene constellation by backcrossing into the C57BL/6 background or to
maintain the A1AR mutation in a two-renin gene background
by backcrossing into the 129J or Swiss strain. Although this genetic
artifact does not limit the conclusion that the A1AR is not
required for mediation of macula densa control of the renin system, it
has to be carefully considered when absolute values of renal renin
content are compared between the genotypes. Inasmuch as a linkage of a
targeted gene and the neighboring gene loci supposedly
unaffected by the knockout procedure potentially occurs in every
knockout model derived from different mouse strains, our results
emphasize the necessity of careful interpretation of data comparing
knockout with wild-type mice.
Taken together, our results support the concept of a tonic inhibitory role of the A1AR on the renin system, but they argue against a role of the A1AR in mediation of the macula densa control of the renin system, as has been demonstrated previously for macula densa control of glomerular filtration.
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ACKNOWLEDGEMENTS |
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We thank Maggy Schweiger and Susanne Lukas for expert technical assistance.
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FOOTNOTES |
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This study was financially supported by Deutsche Forschungsgemeinschaft Grant Schw 778/2-1.
Address for reprint requests and other correspondence: F. Schweda, Institut für Physiologie, Universität Regensburg, 93040 Regensburg, Germany (E-mail: frank.schweda{at}klinik.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.
First published December 10, 2002;10.1152/ajprenal.00280.2002
Received 5 August 2002; accepted in final form 3 December 2002.
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