Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205
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ABSTRACT |
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ANG II exerts a biphasic effect on
Na+ transport in the kidney through its effects on
Na+-K+-ATPase activity. Beginning at
1013 M, ANG II increased
Na+-K+-ATPase activity in freshly isolated rat
proximal tubules to a maximum stimulation at 10
11 M of
1.43 ± 0.08-fold above control. Stimulation decreased
progressively at concentrations >10
10 M to a value of
0.96 ± 0.1-fold at 10
7 M. In the presence of
additional L-arginine, the substrate for NO synthesis, the
stimulatory effect of ANG II (10
11 M) was lost.
Conversely, N-monomethyl-L-arginine
(L-NMMA), the nitric oxide (NO) synthase inhibitor,
unmasked the stimulatory effect of ANG II at 10
7 M
(1.40 ± 0.1-fold).
1H-[1,2,4]oxadiazole-[4,3-a]quinoxalin-1-one, the
soluble guanylyl cyclase inhibitor, like L-NMMA, unmasked the stimulatory effect of ANG II at 10
7 M (1.30 ± 0.1-fold). The intracellular cGMP concentration was increased 1.58 ± 0.28-fold at 10
7 M ANG II. The ANG II AT1
receptor antagonist SK&F 108566 blocked the stimulatory effect of ANG
II at 10
11 M. These data suggest that the NO/cGMP
signaling pathway serves as a negative component in the regulation of
Na+-K+-ATPase activity by ANG II.
N-monomethyl-L-arginine; 1H-[1,2,4]oxadiazole-[4,3-a]quinoxalin-1-one; SK&F 108566; angiotensin II
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INTRODUCTION |
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NA+-k+-atpase, located on the basolateral membrane in the proximal tubule, is the primary mechanism for Na+ reabsorption in the kidney. The ability of ANG II to increase Na+-K+-ATPase activity in the renal proximal tubule is an important regulatory component of Na+ reabsorption (28). The regulation of Na+-K+ATPase by ANG II is mediated by the ANG II AT1 receptor subtype (4, 11, 28). It is recognized that ANG II exerts a biphasic effect on Na+ transport in the kidney. In vitro studies show that at low concentrations (picomolar), ANG II promotes Na+ reabsorption. However, at high concentrations (nanomolar), this stimulatory effect is lost (1). These findings are particularly relevant because peritubular concentrations of ANG II in vivo in the rat are in the 5 to 50 nM concentration range (5, 20, 24).
The effects of ANG II are, at least in part, a direct result of altered Na+-K+-ATPase activity (4). The mechanism behind this biphasic effect of ANG II on Na+-K+-ATPase activity is unclear, but the stimulatory effect on Na+-K+-ATPase activity is thought to be mediated by a pertussis toxin-sensitive G protein pathway (4) coupled to a decrease in intracellular cAMP formation (1, 4).
Nitric oxide (NO) and cGMP antagonize many physiological effects of ANG II such as regulation of blood pressure and Na+ transport. In previous studies, we showed that ANG II, acting through the AT1 receptor, activates the NO/cGMP signaling pathway in the isolated rat proximal tubule (31). Studies by McKee et al. (19) showed that NO and cGMP reduce Na+ transport in the renal cortex by decreasing Na+-K+-ATPase activity. Studies by Liang and Knox (17) showed that NO and cGMP reduce the molecular activity of Na+-K+-ATPase in the cultured opossum kidney cells, thus reducing Na+ transport. Taken together, these studies suggest that the NO/cGMP signaling pathway may be an important physiological regulator of Na+ transport. The purpose of the present study was to examine the role of the NO/cGMP signaling pathway on the ANG II biphasic regulation of Na+-K+-ATPase activity in the rat proximal tubule.
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METHODS |
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Materials and reagents. Collagenase A was purchased from Boehringer Mannheim (Indianapolis, IN). ANG II was purchased from Novabiochem (La Jolla, CA). SK&F 108566 was a generous gift from SmithKline Beecham Pharmaceuticals (King of Prussia, PA). 1H-[1,2,4]oxadiazole-[4,3-a]quinoxalin-1-one (ODQ) was purchased from Alexis (San Diego, CA). IBMX was purchased from Research Biochemicals International (Natick, MA). cGMP immunoassay kit was purchased from Amersham Life Science (Arlington Heights, IL). N-monomethyl-L-arginine (L-NMMA), L-arginine, and other chemicals were purchased from Sigma Chemical (St. Louis, MO).
Isolation of proximal tubules. All animal experiments were approved by the University of Arkansas for Medical Sciences' Animal Care and Use Committee. Animals were housed and killed in accord with the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals (NIH publication 86-23 revised 1985). Rat proximal tubules were isolated from the kidneys of male Sprague-Dawley rats (200-250 g) by collagenase digestion and Percoll density gradient centrifugation using our published methods (21, 31). The buffer used was a modified Krebs buffer (MKB) containing (in mM) 103 NaCl, 5.0 KCl, 2.0 NaH2PO4, 1.0 MgSO4, 1.0 CaCl2, 5.0 glucose, 5.0 malate, 5.0 glutamate, 4.0 lactate, 1.0 alanine, 20 NaHCO3, and 10 HEPES (pH 7.4).
Measurement of cGMP. Isolated tubules were resuspended to a concentration of 1-1.5 mg/ml in MKB and preincubated with the phosphodiesterase inhibitor IBMX (1 mM) for 15 min at 37°C. Aliquots were washed one time and resuspended in the same buffer warmed to 37°C. After a 30-min incubation with ANG II, the reaction was stopped by placing each sample on ice. The aliquots then were centrifuged at 12,000 g for 2 min at 4°C. cGMP content in the cell pellet was assayed by immunoassay as described by the manufacturer. Protein concentration was measured for each sample using a 10% TCA precipitate.
Measurement of Na+-K+-ATPase activity. Na+-K+-ATPase activity was measured in a crude membrane preparation using published methods (2, 14, 17). After the incubation period in phosphate-free MBK, the tubules were allocated into two tubes and frozen in liquid nitrogen. After being thawed, the tubules were centrifuged for 2 min at 8,000 g, and one tube was resuspended in assay buffer (in mM: 100 NaCl, 20 KCl, 4 MgCl2, 100 Tris · HCl, and 2 Na2-ATP) for the measurement of total ATPase activity. The second tube was resuspended in assay buffer containing no K+ and 5 mM ouabain for measurement of ouabain-sensitive ATPase activity, taken as Na+-K+-ATPase activity. Samples were incubated for 15 min at 37°C. The reaction was stopped by immediately returning the reaction mixture to an ice bath and adding ice-cold TCA to a final concentration of 10%. Tubes were then centrifuged at 14,000 g at 4°C for 10 min. The production of Pi was measured using a colorimetric assay as described elsewhere (2, 14, 17). Na+-K+-ATPase activity normalized to protein was calculated as the difference between the total activity (in the absence of ouabain) and the activity remaining after the addition of ouabain.
Measurement of intracellular Ca2+. Intracellular Ca2+ concentration was measured in stirred suspensions of isolated tubules in MKB using the intracellular fluorescent Ca2+ dye fura 2 using our published method (21). Test agents were preincubated for 5 min before the addition of ANG II. The average protein concentration of the tubule suspension was 1.5 mg/ml. The fluorescence signal for each sample was calibrated using digitonin (2%) followed by EGTA (10 mM).
Measurement of lactate dehydrogenase release. Lactate dehydrogenase (LDH) activity was assayed as described by Traylor et al. (26). Extracellular LDH was separated from intracellular LDH by centrifuging aliquots of tubule suspensions through dibutyl phthalate-dioctyl phthalate (2:1). The upper cell-free layer was diluted (1:10) with 2% Triton X-100. Total LDH (extracellular + intracellular) was obtained by diluting (1:10) an aliquot of tubule suspension with 2% Triton X-100. The percentage of LDH release was defined as the extracellular LDH activity expressed as a percentage of the total LDH activity.
Data analysis. Data are reported as means ± SE. Each n represents an individual tubule preparation. Data were analyzed using the t-statistic for comparison between two groups or by a one-way ANOVA followed by the Student-Newman-Keuls test for comparison of more than two groups. P < 0.05 was considered statistically significant.
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RESULTS |
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Biphasic effect of ANG II on Na+-K+-ATPase
activity.
Na+-K+-ATPase activity (ouabain-inhibitable
ATPase activity) was determined after incubation with various
concentrations of ANG II for 30 min in freshly isolated rat proximal
tubules. At the end of the 30-min incubation period, tubule viability,
as measured by LDH release, was 90% or greater. Viability was
unaffected by incubation with ANG II. For example, at concentrations of
107 and 10
11 M, LDH release was 10.5 ± 3.0 and 9.1 ± 3.8%, respectively, compared with a control
value of 9.6 ± 3.3% (n = 4). ANG II caused
maximal stimulation of Na+-K+-ATPase activity
at 10
11 M (1.43 ± 0.08-fold increase above control, Fig.
1). The stimulatory effect began
to decrease with ANG II concentrations >10
10 M. At a
concentration of 10
7 M ANG II,
Na+-K+-ATPase activity was 0.95 ± 0.08%
of control. The control (basal) activity of
Na+-K+- ATPase was 199 ± 16 nmol · min
1 · mg protein
1
(n = 8) and represented ~45-50% of the total
ATPase activity.
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Effect of L-arginine on ANG II-stimulated
Na+-K+-ATPase activity.
The role of NO on ANG II regulation of
Na+-K+-ATPase activity was examined using
L-arginine, the substrate of NO synthesis. L-Arginine (1 mM, ~10-fold higher than physiological
concentration; see Refs. 6 and 23) was preincubated with
the tubules for 5 min before the addition of ANG II.
L-Arginine blocked the stimulatory effect of ANG II at
1011 M (Fig. 2) without
altering basal Na+-K+-ATPase activity in the
proximal tubules (180 ± 7 nmol · min
1 · mg
1,
n = 7, with L-arginine compared with
199 ± 16 nmol · min
1 · mg
1,
n = 8, for control). D-Arginine was used as
a control for L-arginine because D-arginine
cannot be metabolized by NO synthase (NOS) to yield NO. A 5-min
preincubation with D-arginine (1 mM) did not alter the
stimulatory effect of ANG II (10
11 M). Values were
1.43 ± 0.05-fold above control for ANG II (10
11 M)
alone and 1.30 ± 0.02-fold above control for ANG II
(10
11 M) in the presence of D-arginine
(P > 0.05; n = 3). Also,
D-arginine alone had no effect on basal
Na+-K+-ATPase activity.
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Effect of L-NMMA on ANG II-stimulated
Na+-K+-ATPase activity.
To further examine the role of NO on the ANG II regulation of
Na+-K+-ATPase, proximal tubules were incubated
for 5 min with the NOS inhibitor L-NMMA (2 mM; see Ref.
22) before the addition of ANG II. As showed in Fig.
3, L-NMMA restored the
stimulatory effect of ANG II at 107 M (1.44 ± 0.09-fold above control, n = 5, P < 0.05 compared with control) to a value not different from that produced
by 10
11 M ANG II (P > 0.05).
Furthermore, L-NMMA did not affect the stimulatory effect
of 10
11 M (1.32 ± 0.12 in the presence of
L-NMMA). In addition, L-NMMA alone did not
alter basal Na+-K+-ATPase activity in the
proximal tubule (1.07 ± 0.1-fold above control, n = 7, P > 0.05).
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ANG II-stimulated formation of cGMP.
Formation of cGMP was measured 30 min after addition of various
concentrations of ANG II. These data are shown in Fig.
4. ANG II at 107 M
increased cGMP formation to 1.58 ± 0.22-fold above control (n = 5, P = 0.05 compared with
control). ANG II at 10
11 and 10
10 M did not
show any significant increase in cGMP formation (1.09 ± 0.13- and
1.04 ± 0.10-fold above control, n = 5, P > 0.05). The basal levels of cGMP after a 30-min
incubation in the absence of ANG II were 0.68 ± 0.09 pmol/mg
protein (n = 5).
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Effect of soluble guanylyl cyclase inhibition.
The role of cGMP on the regulation of
Na+-K+-ATPase activity by ANG II was examined
using ODQ, the soluble guanylyl cyclase inhibitor (15).
ODQ (50 µM) was preincubated with the tubules for 5 min before the
addition of ANG II (Fig. 5). ODQ restored the stimulatory effect of ANG II at 107 M (1.31 ± 0.07-fold above control, n = 5, P < 0.05 compared with control) to a value not different from that produced
by 10
11 M of ANG II. Furthermore, ODQ did not affect the
stimulatory effect of 10
11 M (1.25 ± 0.12 in the
presence of ODQ). Also, ODQ alone did not alter basal
Na+-K+-ATPase activity in the proximal tubule
(1.11 ± 0.09-fold above control, n = 5, P > 0.05).
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Effects of AT1 receptor antagonism on ANG II-stimulated
Na+-K+-ATPase activity.
Our previous studies showed that the stimulation of NO and cGMP
formation by ANG II (107 M) was mediated by the
AT1 receptor (31). SK&F 108566, the AT1 receptor-selective antagonist (10), was
used to examine the role of AT1 receptors on the regulation
of Na+-K+-ATPase by ANG II. SK&F 108566 was
preincubated for 5 min before the addition of ANG II. These data are
presented in Fig. 6. SK&F 108566 blocked
the stimulatory effect of ANG II at 10
11 M (1.06 ± 0.04-fold above control, n = 4, P > 0.05 compared with control). SK&F 108566 alone did not alter the basal
Na+-K+-ATPase activity in the proximal tubules
(1.14 ± 0.06-fold above control, n = 4, P > 0.05).
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Effects of L-arginine, L-NMMA, and ODQ on
intracellular Ca2+.
Data from our previous studies in the proximal tubule showed that an
increase in intracellular Ca2+ mediated by AT1
receptor activation is associated with NO and cGMP generation
(31). To address the possibility that the site of action
of L-arginine, L-NMMA, or ODQ was at the level
of Ca2+ signaling, their effects on ANG II-induced changes
in intracellular Ca2+ concentration were determined.
L-Arginine, L-NMMA, or ODQ was preincubated for
5 min with fura 2-loaded proximal tubules before the addition of ANG
II. Neither of these agents affected basal intracellular
Ca2+ levels during the 5-min incubation period. The rise in
intracellular Ca2+ concentration elicited by ANG II
(107 M) was 244 ± 58 nM (n = 3)
above basal levels. Neither agent had any effect on the rise in
intracellular Ca2+ concentration elicited by ANG II (data
not shown).
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DISCUSSION |
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ANG II is an important regulator of Na+ transport in the kidney. Interestingly, ANG II exerts a biphasic regulation on proximal tubule Na+-K+-ATPase activity (4). At picomolar concentrations, ANG II stimulates Na+-K+-ATPase activity, whereas at nanomolar concentrations stimulation is lost. Bharatula and co-workers (4) showed that stimulation of Na+-K+-ATPase activity by ANG II was mediated by AT1 receptors coupled to the inhibition of adenylyl cyclase via a pertussis toxin-sensitive G protein. It is proposed that the decrease in cAMP formation can result in decreased phosphorylation of Na+-K+-ATPase through protein kinase A (1, 3, 11). Additional studies have also shown that phosphorylation of the pump by protein kinase A or protein kinase C can decrease activity (7, 12). Thus inhibition of cAMP may explain the stimulatory effects of ANG II at picomolar concentrations. The present data suggest that activation of NO/cGMP signaling is responsible, at least in part, for the loss of the stimulatory effects of ANG II at nanomolar concentrations.
In a previous study, we showed that activation of AT1
receptors led to a rise in intracellular Ca2+ concentration
and the activation of cGMP formation in the rat proximal tubule
(31). Studies by McKee et al. (19) showed that NO and cGMP reduced Na+ transport in the rat renal
cortex by decreasing Na+-K+-ATPase activity.
They further showed the regulation of
Na+-K+-ATPase activity involved cGMP- and
cGMP-dependent protein kinase. Studies by Liang and Knox
(17) reported that NO and cGMP reduced the molecular
activity of Na+-K+-ATPase activity in the
cultured opossum kidney cells. They also showed that NO donors acting
through the cGMP pathway can activate protein kinase C-, resulting
in the inhibition of Na+-K+-ATPase activity
(16). Studies with the NO donor sodium nitroprusside have
suggested that NO inhibits both basal and ANG II-stimulated fluid
absorption by the proximal tubule (13). However, in other studies, sodium nitroprusside was shown to produce a biphasic effect on
fluid absorption in the absence of ANG II (27). Our studies reveal that endogenous synthesis of NO and the activation of
the NO/cGMP signaling pathway by ANG II represents an important physiological modulator of proximal tubule
Na+-K+-ATPase activity.
The following three approaches were used to evaluate the role of NO
signaling: 1) increasing the substrate for NOS,
2) inhibiting NOS activity, and 3) inhibiting
cGMP synthesis. Rat proximal tubules express a constitutive
Ca2+-regulated NOS (9, 18). In a previous
study, we showed that ANG II at concentrations >1010 M
increase intracellular Ca2+ concentration and the
generation of cGMP (31). However, we and others have shown
that basal levels of intracellular Ca2+ are enough to
support low levels of spontaneous NO generation and cGMP formation
(26, 29-31). Freshly isolated rat proximal tubules
are capable of generating NO even in the absence of added L-arginine (26, 29-31) because, as the
primary site of L-arginine biosynthesis (8),
they can carry enough intracellular L-arginine for NO
synthesis (23). Although intracellular
L-arginine concentration in freshly isolated rat proximal
tubules is reported to be ~2 µmol/mg protein (23), the
intracellular concentration of L-arginine available for NO
synthesis is not known. Nevertheless, the addition of
L-arginine can increase NO synthesis (25, 30).
Because L-arginine did not affect intracellular
Ca2+ levels, a likely explanation for the inhibitory
effects of added L-arginine is increased NO synthesis. This
is supported by the lack of inhibitory effect of D-arginine
on the ANG II response.
In the present study, we show that activation of NOS opposes the
stimulatory effects of ANG II on Na+-K+-ATPase
activity. This is supported by the observation that increasing the
substrate for NOS prevents the stimulatory effects of ANG II at a
concentration (1011 M) that under control conditions
activates Na+-K+-ATPase activity. In contrast,
the NOS inhibitor L-NMMA unmasks the stimulatory effect of
ANG II (10
7 M). Thus modulation of NO synthesis modulates
the effects of ANG II on Na+-K+-ATPase
activity. The ability of the soluble guanylyl cyclase inhibitor ODQ to
also unmask the stimulatory effect of ANG II suggests that the effects
of NO are mediated by cGMP. As expected, neither L-NMMA nor
ODQ affected the stimulatory effects of ANG II at 10
11 M,
a concentration that did not cause an increase in cGMP. To confirm that
L-NMMA, ODQ, and L-arginine were acting at the
level of NO and not AT1 receptors, we showed that these
agents did not affect the ANG II-stimulated rise in intracellular
Ca2+ concentration.
Interactions between the NO/cGMP signaling and the ANG II signaling
pathways in the proximal tubule appear to be an example of a
homeostatic mechanism to regulate Na+-K+-ATPase
activity. This occurs through activation of AT1 receptors coupled to a rise in intracellular Ca2+ concentration as
the concentrations of ANG II rise above 1010 M
(EC50 for ANG II is 1.7 nM; see Ref. 31). The
nonpeptide AT1 receptor antagonist SK&F 108566 has been
well characterized in other tissues as a selective AT1
antagonist (10). SK&F 108566 blocks the stimulatory
effects of high concentrations of ANG II on intracellular
Ca2+ concentration and the generation of cGMP in the
proximal tubule (31). We now show that SK&F 108566 also
blocks low concentrations of ANG II that stimulate
Na+-K+ATPase activity. Thus the studies
with SK&F 108566 indicate that AT1 receptors mediate both
the stimulation of Na+-K+-ATPase activity and
the activation of NO synthesis. NO/cGMP signaling serves to dampen the
effects of increasing concentrations of ANG II. As the concentration of
ANG II rises to critical levels above 10
10 M, NO
synthesis is triggered. This results in cGMP generation and inhibition
of Na+-K+-ATPase activity. Because peritubular
concentrations of ANG II are in the nanomolar concentration range
(5, 20, 24), our data suggest that the effects of
fluctuations in ANG II concentration on
Na+-K+-ATPase activity are buffered by the
activation of NO/cGMP signaling. The interaction between these two
signaling pathways may represent an important physiological mechanism
to regulate Na+-K+-ATPase activity in the
proximal tubule.
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ACKNOWLEDGEMENTS |
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This work was supported in part by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-44716 to P. R. Mayeux, Committee for Allocation of Graduate Student Research Funds of University of Arkansas for Medical Sciences, and an American Heart Association Heartland Affiliate Predoctoral Fellowship to C. Zhang.
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FOOTNOTES |
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Address for reprint requests and other correspondence: P. R. Mayeux, Dept. of Pharmacology and Toxicology, Univ. of Arkansas for Medical Sciences, 4301 West Markham St., slot 611, Little Rock, AR 72205 (E-mail: mayeuxphilipr{at}exchange.uams.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.
Received 9 May 2000; accepted in final form 6 November 2000.
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