(Hypertension. 2000;35:643.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Age-Related Changes in Renal Cyclic Nucleotides and Eicosanoids in Response to Sodium Intake
From the Department of Internal Medicine, University of Virginia Health System, Charlottesville, Va.
Correspondence to Helmy M. Siragy, MD, Department of Internal Medicine, Box 482, University of Virginia Health System, Charlottesville, VA 22908. E-mail hms7a{at}virginia.edu
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Abstract |
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Abstract—The signaling molecules cGMP, cAMP, prostaglandin E2 (PGE2), and prostaglandin F2
(PGF2) play important roles in mediating the response of
the kidney to changes in dietary sodium intake. We used a renal
microdialysis technique in conscious rats to address the hypothesis
that the renal ability to produce these mediators in response to
dietary sodium intake is altered during maturation. Young (4-week-old)
or adult (6-month-old) rats were studied after the consumption for 5
days of diets containing low (0.04% NaCl), normal (0.28% NaCl), or
high (4.0% NaCl) levels of sodium. Plasma renin activity was
significantly increased by low-sodium diet and significantly decreased
by high-sodium diet, with no significant difference between the
responses of the 2 age groups. Renal interstitial fluid
(RIF) levels of cGMP, cAMP, PGE2, and PGF2
on normal-sodium diet were similar in the 2 age groups. Low-sodium diet
caused a significant increase in RIF levels of all 4 mediators, with no
significant differences between the responses of the 2 age groups.
High-sodium diet also caused a significant increase in RIF levels of
all 4 mediators. However, RIF production of cGMP, cAMP, and
PGE2 was significantly greater, and RIF PGF2
production was significantly lower, in young rats compared with
adult rats. These data demonstrate that the kidneys of young and adult
rats respond to dietary sodium restriction in a similar manner but that
there are age-related changes in the renal response to sodium
loading.
Key Words: age • cyclic AMP • cyclic GMP • kidney • prostaglandins • sodium • rats
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Introduction |
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The kidney plays a pivotal role in maintaining a constant total body sodium and extracellular fluid volume in the face of changing levels of sodium intake. Increasing age is associated with a number of changes in renal function, including a reduced ability to excrete salt and water loads.1 The frequency and severity of hypertension increases with age, and even in the absence of hypertension, an increase in the salt sensitivity of blood pressure over time has been observed.2 Several lines of evidence suggest not only that renal function is altered before the development of hypertension but also that renal dysfunction is a requirement for hypertension to develop.3 4 Hence, the decline in renal function with increasing age may explain the increased incidence of hypertension with age.
Given that hypertension is more common in adults than in children, we
hypothesized that the ability of the kidney to respond to changes in
dietary sodium intake may be altered during maturation. Previous
studies of the effect of age on renal function have often examined the
urinary content of mediators, such as nitric oxide (NO), cyclic
nucleotides, and eicosanoids, as an estimate of renal
levels of synthesis. However, urinary excretion levels may not directly
correlate with renal production because of extrarenal sites of
production and alterations in tubular
reabsorption.5 Therefore, in the present study, we
used a renal interstitial fluid (RIF) microdialysis
technique to directly determine the intrarenal levels of several
mediators that play important homeostatic roles in the kidney. We
examined the levels of cortical RIF cGMP, cAMP,
prostaglandin E2
(PGE2), and prostaglandin
F2 (PGF2) produced by
young (4-week-old) and adult (6-month-old) Sprague-Dawley rats in
response to increased or decreased dietary sodium intake.
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Methods |
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Renal Microdialysis Technique
For the determination of RIF cGMP, cAMP, PGE2, and PGF2
, we
constructed renal microdialysis probes with a molecular mass cutoff of
10 kDa, as previously described.6 7 8 9 The best in vitro
recovery rates for all compounds analyzed were obtained with a
perfusion rate of 3 µL/min and were 70% for cGMP,7 68%
for cAMP, 63% for PGE2,7 and 60%
for PGF2.9
Animal Preparation
Experiments were conducted with 4-week-old (young group) and
6-month-old (adult group) female Sprague-Dawley rats (n=10 per age
group) purchased from Harlan Teklad (Madison, Wis). Both groups were
housed under controlled conditions (temperature 21±1°C, humidity
60±10%, and lighting from 8:00 AM to 8:00
PM). All procedures were conducted with the approval of the
Animal Research Committee of the University of Virginia.
For the implantation of microdialysis probes, rats were anesthetized with ketamine (80 mg/kg IM) and xylazine (8 mg/kg IM), and the right and left kidneys were exposed via a midline abdominal incision. Microdialysis probes were placed in the cortex of both kidneys, as previously described.6 7 8 9 To obtain vascular access, a heparinized polyethylene tube was inserted into the right jugular vein. This tube was flushed daily with 10% heparin in 5% dextrose in water and was capped with a small piece of copper wire. After surgery, rats were allowed 7 days for recovery before experiments began.
Experiments were started at the same time (8:00 AM) each day to avoid any diurnal variation of the measured parameters. For RIF collection, the inflow tube of each dialysis probe was connected to a syringe filled with lactated Ringer’s solution and perfused at 3 µL/min. After a 30-minute equilibration period, the effluent from the outflow tube was collected for four 30-minute sampling periods into plastic tubes. Samples were stored at -80°C until the time of assay.
Effect of Low, Normal, or High Dietary Sodium Intake
During the 7-day recovery period after surgery, rats consumed a
normal-sodium diet (0.28% NaCl). At the end of the recovery period,
systolic blood pressure (SBP) was measured by tail-cuff
plethysmography (Rat Tail Monometer-Tachometer system, Natsume model
KN-210, Peninsula Laboratories), and RIF samples were collected. After
the last RIF collection period, a 0.5 mL blood sample for measurement
of plasma renin activity (PRA) was withdrawn from the jugular vein
catheter of each rat into an EDTA-containing tube. Plasma was separated
by centrifugation and stored at -80°C. Rats then
consumed either a low-sodium diet (0.04% NaCl) or a high-sodium diet
(4.0% NaCl), in random order. Each diet was consumed for 5 days, after
which SBP was measured again, and further RIF and plasma samples were
collected from each rat. At the end of the study, each kidney was
examined to verify the location of the dialysis fibers.
Analytical Methods
RIF cGMP, cAMP, PGE2, and
PGF2 levels in dialysate samples were measured
by use of enzyme immunoassay kits (Cayman Chemical Co). The
sensitivities and specificities of the immunoassays were, respectively,
0.11 pmol/mL and 100% for cGMP, 1.1 pmol/mL and 100% for cAMP, 114
pg/mL and 100% for PGE2, and 14.2 pg/mL and
100% for PGF2. Cross-reactivity with other
cyclic nucleotides was <0.01% for both the cGMP and the
cAMP assay. Cross-reactivities of the PGE2 and
PGF2 assays with other eicosanoids were
<0.01% and 5%, respectively, with PGD2 and
<2% with other eicosanoids for the PGF2
assay. PRA was determined by radioimmunoassay,10 and
activity was expressed as nanograms angiotensin (Ang) I
generated per milliliter plasma per hour.
Statistical Analysis
Comparisons between different diets were examined by ANOVA,
including repeated-measures analysis, with the use of the
general linear models procedure of the Statistical Analysis
System. Multiple comparisons of individual pairs of effect means were
conducted by the use of least squares pooled variance. Data are
expressed as mean±SE. A value of P<0.05 was considered
statistically significant.
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Results |
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Blood Pressure Response to Changes in Dietary Sodium Intake
During normal-sodium intake, there was no significant difference in SBP between young and adult rats (106±1.5 and 107±1.8 mm Hg, respectively). The consumption of a low- or high-sodium diet for 5 days did not significantly alter the SBP of either young or adult rats (low-sodium diet 107±1.5 and 107±1.7 mm Hg, respectively; high-sodium diet 107±1.5 and 107±1.5 mm Hg, respectively).
PRA in Response to Changes in Dietary Sodium Intake
During normal-sodium intake, there was no significant difference
in PRA between young and adult rats (1.6±0.5 and 1.5±0.6 ng/mL per
hour, respectively) (Figure 1).
The consumption of a low-sodium diet for 5 days resulted in a
significant (P<0.0001) increase in PRA in both young and
adult rats (7.8- and 8.7-fold increase, respectively). In contrast, the
consumption of a high-sodium diet for 5 days resulted in a significant
(P<0.0001) decrease in PRA in both young and adult rats
(5.3- and 7.5-fold decrease, respectively). There were no significant
differences between the PRA values of young and adult rats on either of
the altered sodium diets.
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RIF Cyclic Nucleotide Levels in Response to Changes in
Dietary Sodium Intake
During normal sodium intake, there was no significant
difference in either RIF cGMP or RIF cAMP production between
young and adult rats (cGMP 1.3±0.4 and 0.9±0.5 pmol/min,
respectively; cAMP 1.3±0.5 and 1.0±0.5 pmol/min,
respectively) (Figure 2). The consumption
of a low-sodium diet for 5 days resulted in a significant
(P<0.0001) increase in RIF cGMP and cAMP production
in both young and adult rats (cGMP 1.9- and 2.1-fold increase,
respectively; cAMP 2.0- and 2.2-fold increase, respectively). There
were no significant differences in RIF cGMP and cAMP concentrations
between young and adult rats after 5 days of low-sodium diet. The
consumption of a high-sodium diet for 5 days also caused a significant
(P<0.0001) increase in RIF cGMP and cAMP production
in both young and adult rats (cGMP 3.0- and 2.2-fold increase,
respectively; cAMP 5.1- and 3.9-fold increase, respectively). In
contrast to the effects of a low-sodium diet, the amounts of RIF cGMP
and cAMP produced by young rats after 5 days of high-sodium diet were
significantly higher than the amounts produced by adult rats on the
same diet (P<0.001).
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RIF Eicosanoid Levels in Response to Changes in Dietary Sodium
Intake
During normal-sodium intake, there was no significant difference
in either RIF PGE2 or RIF
PGF2 production between young and
adult rats (PGE2 1.1±0.6 and 0.9±0.4 pg/min,
respectively; PGF2 0.7±0.4 and 1.8±0.5
pg/min, respectively) (Figure 3). The
consumption of a low-sodium diet for 5 days resulted in a significant
(P<0.0001) increase in RIF PGE2 and
PGF2 production in both young and
adult rats (PGE2 4.6- and 5.0-fold increase,
respectively; PGF2 18.0- and 6.2-fold
increase, respectively). There were no significant differences in RIF
PGE2 and PGF2
concentrations between young and adult rats after 5 days of low-sodium
diet. The consumption of a high-sodium diet for 5 days also caused a
significant (P<0.0001) increase in RIF
PGE2 and PGF2
production in both young and adult rats
(PGE2 7.0- and 5.4-fold increase, respectively;
PGF2 3.1- and 2.6-fold increase,
respectively). Similar to the changes in cyclic nucleotide
production, the amounts of RIF PGE2
produced by young rats after 5 days of high-sodium diet were
significantly higher than the amounts produced by adult rats on the
same diet (P<0.001). In contrast, the amounts of RIF
PGF2 produced by young rats after 5 days of
high-sodium diet were significantly lower than the amounts produced by
adult rats on the same diet (P<0.001).
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Discussion |
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The major findings of the present study are that young and adult rats respond to dietary sodium restriction in a similar manner, with significant increases in the renal production of the cyclic nucleotides cGMP and cAMP and the eicosanoids PGE2 and PGF2
. In
contrast, a high dietary sodium intake resulted in significantly
increased renal production of cGMP, cAMP, and
PGE2 and significantly decreased renal
production of PGF2 in young rats
compared with adult rats. After 5 days of dietary sodium restriction, we observed a 2-fold increase in RIF cyclic nucleotide levels in both young and adult rats. We have previously shown that sodium depletion results in increased cortical production of cGMP.7 This increase is mediated by elevated Ang II produced because of the activation of the renin-angiotensin system during sodium depletion. Ang II acts via the Ang II type 2 (AT2) receptor to stimulate renal production of bradykinin, which activates endothelial NO synthase and leads to increased production of NO and its downstream mediator cGMP.8 11 These responses enable increased renal production of the vasodilator cGMP, which counterbalances the greatly increased renal Ang II levels produced during sodium restriction. Dietary sodium restriction is also typically associated with increased pituitary production of the antidiuretic hormone vasopressin. Stimulation of the vasopressin V2 receptor on renal epithelial cells leads to activation of adenylyl cyclase12 and may be responsible for the increased RIF cAMP levels observed. In addition, a low-sodium diet was associated with increased RIF PGE2 levels. Within the kidney, PGE2 interacts with 4 distinct G protein–coupled receptors known as EP1 to EP4. The EP2 receptor, which stimulates adenylyl cyclase, has been localized to the glomeruli.13 Therefore, it seems likely that the elevated RIF cAMP levels observed during sodium restriction in the present study occurred in response to increased production of both vasopressin and PGE2.
We found that 5 days of dietary sodium restriction resulted in a
significant increase in RIF eicosanoid levels in both young and adult
rats. We have previously shown that sodium depletion causes an increase
in RIF PGE2 levels; this increase was mediated
via Ang II stimulation of the Ang II type 1 (AT1)
receptor.7 Furthermore, sodium depletion is associated
with an increase in renal conversion of PGE2 to
PGF2, an effect mediated via the
AT2 receptor.9
PGE2 plays a major role in the inhibition of
tubular sodium reabsorption, thus leading to increased sodium
excretion. The increased renal conversion of PGE2
to PGF2 during sodium depletion is thus
thought to be a protective mechanism to prevent sodium
wasting.9
Taken together, these results indicate that the adult kidney is able to
respond as effectively as the young kidney to dietary sodium
restriction. Renal cGMP, cAMP, and PGE2 increase
as a protective measure to counterbalance the increased Ang II levels.
To prevent overcompensation by excessive PGE2
activity, there is also an increase in the conversion of
PGE2 to the vasoconstrictor
PGF2. All of these homeostatic mechanisms
appear to be active in the adult kidney and in the young kidney to a
similar degree.
In contrast to the results obtained during dietary sodium restriction, we found that young rats produced significantly higher levels of RIF cyclic nucleotides in response to a high-sodium diet than did adult rats. A well-established mediator of increased renal cGMP production during high-sodium intake is atrial natriuretic peptide (ANP), which acts via the type A guanylyl cyclase–linked natriuretic peptide receptor to stimulate renal cGMP formation. It seems unlikely, however, that a reduced production of ANP could account for the decreased cGMP response to sodium loading in adult rats, in view of the fact that previous studies have reported no difference in either basal or stimulated plasma ANP levels between young and mature rats.14 15 Similarly, a reduced renal cGMP response to ANP stimulation is not a likely explanation, because the acute infusion of ANP conversely causes a greater increase in urinary cGMP excretion in 10-week-old than in 4-week-old rats.16 Another potential explanation for the increased RIF cGMP levels observed during high-sodium intake is increased cortical NO production. Indeed, glomeruli isolated from rats consuming a high-sodium diet for 4 days show an increase in both endothelial NO synthase expression and calcium-dependent NO production.17 Although an effect of age on this response to sodium loading has not yet been reported, it is tempting to speculate that the kidneys of adult rats may have a reduced capacity to produce NO during high-sodium intake, thus resulting in the reduced RIF cGMP levels observed in the present study.
It is likely that the increased renal cAMP production observed during high-sodium intake was at least in part due to an increase in renal dopamine levels. Dopamine, produced by decarboxylation of circulating dopa by the renal proximal tubule, acts via D1-like receptors to stimulate adenylyl cyclase and mediate renal vasodilatation, natriuresis, and diuresis in response to sodium loading.18 A possible explanation for the decreased RIF cAMP response to high-sodium diet in adult rats compared with young rats is the finding that the kidneys of aged rats show a reduced tubular uptake of circulating dopa, resulting in lower renal dopamine levels.19 Renal production of adenosine is also markedly increased in both the cortex and medulla during high-sodium intake.6 Within the kidney, adenosine both inhibits adenylyl cyclase via the antinatriuretic A1 receptor and stimulates adenylyl cyclase via the natriuretic A2A and A2B receptors. In view of the recent finding20 that salt loading downregulates renal expression of the A1 receptor, without altering expression of the A2A and A2B receptors, it seems likely that adenosine contributes to the increased RIF cAMP levels observed in response to a high-sodium diet. Therefore, it will be of interest in the future to determine whether age affects this renal adenosine receptor response to increased sodium load.
In the present study, a high-sodium diet and a low-sodium diet were found to increase cortical RIF PGE2 levels to a similar degree. It is likely that the increased production of the vasodilator eicosanoid during high sodium intake enhances the ability of the kidney to excrete the sodium load. In addition to the direct conversion of arachidonic acid by the cyclooxygenase enzymes, prostaglandin release may be induced by cytochrome P450–dependent metabolites of arachidonic acid.21 Thus, it is possible that the increased RIF PGE2 levels observed in the present study were due to salt-induced upregulation of renal cytochrome P450.22 In this regard, it is of interest that renal cytochrome P450–dependent metabolism of arachidonic acid has been found to decline during maturation,23 thus providing a potential explanation for the present finding that young rats produce significantly greater amounts of PGE2 in response to high-sodium diet than do adult rats. Moreover, the increased RIF PGE2 produced by young rats during high-sodium intake is likely to act via the EP2 receptor to contribute to the increased RIF cAMP levels observed. Indeed, the importance of the EP2 receptor in the renal response to sodium loading was recently demonstrated by the finding that mice deficient in this receptor develop hypertension in response to a high-sodium diet.24
Unlike the changes in RIF PGE2, the increases in
RIF PGF2 production were much smaller
in response to a high-sodium diet than to a low-sodium diet. This is
likely to reflect a reduced activity of the enzymes responsible for the
conversion of PGE2 to
PGF2, in view of the fact that this activity
is known to be stimulated by Ang II via the AT2
receptor.9 PGF2 exerts a
vasoconstrictor influence on the renal vasculature, in opposition to
the vasodilatory effects of PGE2. Therefore, a
reduction in the conversion of PGE2 to
PGF2 during high-sodium intake enables the
natriuretic effects of PGE2 to
predominate, thus eliminating the increased sodium load. In adult rats,
RIF PGF2 production in response to
high-sodium diet was significantly greater than that in young rats,
suggesting that the conversion of PGE2 to
PGF2 is downregulated to a lesser extent in
adult rats than in young rats. An increased conversion of
PGE2 to PGF2 in adult
rats would also account for the decreased RIF
PGE2 levels observed in adult rats compared with
young rats on a high-sodium diet. The mechanism underlying the
increased conversion in adult rats is unclear, because the
renin-angiotensin system was suppressed to a similar degree
by a high-sodium diet in both young and adult rats; thus, Ang II levels
would be very low in both groups. Nevertheless, these changes result in
an increase in the
PGF2-to-PGE2 ratio in
adult rats, which would be predicted to reduce the degree of
natriuresis produced in response to the sodium load.
Overall, these results suggest that compared with the young kidney, the
adult kidney has an altered response to high-sodium intake. In the
young kidney, cGMP, cAMP, and PGE2
production increase, and the ratio of
PGF2 to PGE2 decreases
in response to sodium intake, all of which enable the kidney to
eliminate the excess sodium load and thus maintain a constant total
body sodium. Although the adult kidney also responds to high-sodium
intake with an increase in cGMP, cAMP, and PGE2,
these increases are significantly decreased compared with those in the
young kidney, and there is an increase in the ratio of
PGF2 to PGE2. Despite
the alterations in the renal response to sodium loading in adult
compared with young rats, we observed no difference in SBP between the
2 groups of rats, regardless of the level of sodium intake. This was in
contrast to previous studies reporting that the blood pressure of
4-week-old Sprague-Dawley and Wistar-Kyoto rats is less than that of
adult (10- to 12-week-old) rats.16 25 The reason for this
discrepancy is unclear but may be related to the fact that the previous
studies used anesthetized rats, whereas in the present
study, blood pressure was measured in conscious rats.
In conclusion, the results of the present study demonstrate that compared with the young kidney, the adult kidney has an altered capacity to respond to stresses such as sodium loading. This may help to explain the phenomenon of declining renal function and increasing incidence of hypertension with age.
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Acknowledgments |
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This study was supported by American Heart Association Fellowship F98266V (to Dr Millatt) and by grants HL-47669 and HL-57503 from the National Institutes of Health (to Dr Siragy). Dr Siragy is the recipient of Research Career Development Award K04-HL-03006 from the National Institutes of Health.
Received June 9, 1999; first decision July 6, 1999; accepted September 13, 1999.
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