(Hypertension. 1998;32:1054-1059.)
© 1998 American Heart Association, Inc.
Scientific Contributions |
Bromocriptine Regulates Angiotensin II Response on Sodium Pump in Proximal Tubules
From the Institute for Cardiovascular Studies, College of Pharmacy, University of Houston, Houston, Tex.
Correspondence to Dr Mustafa F. Lokhandwala, Professor of Pharmacology, College of Pharmacy, University of Houston, Houston, TX 77204-5511. E-mail MLokhandwala{at}uh.edu
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Abstract |
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Abstract—Dopamine and angiotensin II (Ang II) receptors have been reported to exhibit an interaction in renal proximal tubules. The present study was designed to investigate the regulation by a D2-like dopamine receptor of Ang II–mediated stimulation of Na,K-ATPase activity in the renal proximal tubules. Ang II (10-13 to 10-9 mol/L) stimulated Na,K-ATPase activity in the proximal tubules that was completely abolished when the tubules were pretreated with the D2-like receptor agonist bromocriptine (1 µmol/L) for 30 minutes. The effect of bromocriptine on Ang II response was prevented by domperidone (1 µmol/L), a D2-like dopamine receptor antagonist. Similarly, the inhibition of forskolin (1 µmol/L)–induced cAMP accumulation caused by Ang II (10 pmol/L) was also abolished in bromocriptine-pretreated tubules. Basal and forskolin-stimulated cAMP was not significantly different in bromocriptine-treated tubules compared with the control. [3H]-Ang II binding sites (angiotensin type 1 [AT1] receptors) were reduced by
65% in
bromocriptine-treated proximal tubules, a result that was further
substantiated by Western blot analysis revealing a 50%
decrease in AT1 receptors in bromocriptine-treated tubules
compared with the control. Western blot analysis of G proteins
revealed a 2-fold increase in Gs
and a 20% decrease in
Gi1 and Gi2 in the
bromocriptine-treated proximal tubules. Bromocriptine (1 µmol/L)
alone stimulated Na,K-ATPase activity during the first 30 minutes of
incubation, and thereafter the stimulation fell to the basal level.
Similarly, bromocriptine-mediated inhibition of cAMP lasted only up to
20 minutes. The data suggest that preactivation of D2-like
dopamine receptors abolishes Ang II–mediated stimulation of
Na,K-ATPase activity and inhibition of cAMP accumulation. This
phenomenon may be a consequence of a decrease in AT1
receptors and alterations in G protein levels in the proximal tubules.
We propose that such a regulation of Ang II response by bromocriptine
is the result of heterologous desensitization of the
D2-like receptor system.
Key Words: receptor, dopamine • receptor, angiotensin • sodium pump • G protein • kidney tubules, proximal
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Introduction |
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Angiotensin (Ang) II and dopamine are 2 important regulators of sodium and water transport across the renal proximal tubules.1 2 Ang II receptors, mainly angiotensin type 1 (AT1) subtypes, have been shown to exist on both basolateral and brush border membranes.3 4 The activation of AT1 receptors by Ang II (picomolar) causes an increase in sodium reabsorption by proximal tubules.5 6 The activation of dopamine receptors, also present on the proximal tubules, leads to an inhibition of the tubular transport of sodium and thus promotes sodium and water excretion.7 8 The opposing actions of Ang II and dopamine on sodium transport result from the opposite effects of these hormones on sodium-transporting enzymes, ie, Na,H-exchanger on the brush border and Na,K-ATPase on the basolateral membranes. Whereas Ang II (pmol/L) causes activation of Na,H-exchanger and Na,K-ATPase activities, dopamine produces inhibition of these enzyme activities by activating D1-like dopamine receptors.9 10 11 12 Because of the opposite actions on tubular sodium transport of these 2 hormones, intrarenally produced Ang II has been shown to oppose the natriuretic response to D1-like receptor agonist in rats.13 Dopamine and the agonists at D1-like and D2-like receptors alone have been reported to antagonize the actions of Ang II on 22Na uptake by brush border vesicles and to decrease the Ang II binding sites on the vesicles.14 Cheng et al15 reported that dopamine, by activating D1-like receptors, decreases the expression of AT1 receptors in cultured proximal tubule cells, an effect likely mediated by increased intracellular cAMP.
Recently, we have shown that Ang II (pmol/L) stimulated Na,K-ATPase activity in the proximal tubules through a pertussis toxin–sensitive G protein (likely Gi) and the inhibition of the cAMP pathway.16 Similarly, D2-like receptor agonist bromocriptine produced stimulation of Na,K-ATPase activity through a pertussis toxin–sensitive G protein and the inhibition of the adenylyl cyclase–linked pathway in the proximal tubules and in murine cells transfected with D2Long receptor cDNA.17 18 These findings demonstrate that the stimulatory action of Ang II and bromocriptine on Na,K-ATPase activity share the adenylyl cyclase–linked cellular signaling mechanism as a common pathway. We hypothesized that the effect of D2-like dopamine receptor agonist on the attenuation of Ang II response may be because of a mechanism related to heterologous desensitization process. Therefore, in the present study, Ang II–mediated stimulation of Na,K-ATPase activity was examined in the bromocriptine-pretreated proximal tubules, and subsequently Ang II binding, AT1 receptors, G proteins, and cAMP were measured to investigate the mechanism of AT1 Ang II and D2-like dopamine receptor interaction.
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Methods |
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Male Sprague-Dawley rats of
200 g weight (Harlan
Sprague-Dawley, Inc, Indianapolis, Ind) were purchased and housed in
plastic cages in an air-conditioned animal care facility. The animals
were fed with standard rat chow (Purina Mills) and given tap water
ad libitum.
Isolation and Enrichment of Renal Proximal Tubules
Rats were anesthetized with sodium pentobarbital (50
mg/kg IP). Renal cortical tubular suspensions were prepared according
to the method of Gesek et al,19 with slight
modifications adopted in our laboratory.20
Protein was assayed by use of a kit from Pierce, and bovine serum
albumin was used as standard.
Na,K-ATPase Assay
The proximal tubular suspension (1 mg protein/mL) was divided
into 2 sets: one was incubated with bromocriptine (1 µmol/L) and
the other served as control. After incubation at 37°C for 30 minutes
in a shaking water bath, Ang II was added (10-13
to 10-9 mol/L) to both sets, and the incubation
was continued for another 30 minutes (a total of 60 minutes of
bromocriptine presence). In another set of experiments, the tubules
were incubated with bromocriptine (1 µmol/L) for varying time
periods (10 to 60 minutes) to examine the effect of time on Na,K-ATPase
stimulation by bromocriptine. After incubation, the tubules were made
permeable by rapid freezing in dry ice/acetone and thawing.
Subsequently, Na,K-ATPase activity was measured by the method of
Quigley and Gotterer,21 adopted in our laboratory
with slight modifications.20 Na,K-ATPase activity
was expressed as nanomoles Pi per milligram
of protein per minute.
cAMP Assay
The treatment of proximal tubular suspension (7 to 8 mg/mL
protein) was performed in a way similar to that described in the
previous section. Two sets of tubules were incubated with bromocriptine
(1 µmol/L) for 30 minutes at 37°C in a shaking water bath;
then Ang II was added and the incubation was continued for another 30
minutes. All the incubations were performed in the presence of
forskolin (1 µmol/L). The tubules were also incubated with
bromocriptine for varying periods of time (5 to 60 minutes). The
reaction was terminated by putting the samples in a boiling water bath
for 3 to 5 minutes. The samples were centrifuged, and the
supernatant was used for cAMP measurement as we have described
earlier.17 The values of cAMP were calculated and
expressed as picomoles per milligram of protein by use of the cAMP
standard curve (0.25 to 8 pmol) run in parallel.
Receptor-Ligand Binding
The proximal tubules were treated with bromocriptine for 60
minutes, which was the total amount of bromocriptine exposure time in
Na,K-ATPase and cAMP assay protocols. The samples were
homogenized in 10 mmol/L Tris-HCl buffer containing
1 mmol/L MgCl2 and 2 mmol/L PMSF
(buffer A) and centrifuged at 34 000g for 30
minutes followed by 2 washes with buffer A. Finally, the pellets as the
proximal tubular membranes were collected and suspended in
Tris-HCl buffer, 50 mmol/L, pH 7.4, containing 1 mmol/L
MgCl2 (buffer B) and used for ligand binding as
well as for Western blot analysis of AT1
receptors and G proteins (described below).
For binding, we incubated 10 to 12 nmol/L
(Kd of Ang II for AT1
receptor) of [3H]-Ang II with 50 µg of
proximal tubular membrane in buffer B. To determine the nonspecific
binding, we added cold Ang II (1 µmol/L) to the binding assay.
The binding was terminated by rapid filtration under vacuum using GF/C
glass fiber filters followed by 3 washes of 4 mL each with buffer B.
The filter papers were extracted in scintillation fluid, and the
radioactivity was counted in liquid scintillation counter at an
efficiency of 60%. Nonspecific binding was 20% of the total
[3H]-Ang II binding.
Western Blot Analysis of AT1 Receptors and
G Proteins
The proteins were solubilized in Laemmli buffer, and 25
µmol/L proteins (control and treated) were resolved by
SDS–polyacrylamide gel (10%) electrophoresis. The resolved
proteins were electrophoretically transferred onto immobilon P membrane
(blot). The blot was incubated with polyclonal
affinity-purified antibodies for AT1 receptor,
Gs, Gi1/2, or
Gq/11, for 1 hour. After 3 washes in
Tris-buffered saline, the blot was incubated with anti-rabbit
IgG-horseradish peroxidase conjugate. The signal was detected using
chemiluminescent substrate and recorded on x-ray film. Density of
the bands was analyzed using a Sharp color scanner. Prestained
markers were used for calculating the molecular weight of the bands and
to ascertain the transfer of proteins from the gel.
The antibodies are polyclonal, purified, and antipeptides. The amino
acid sequence of the peptides, which is specific to the respective
proteins, is as follows: QDDCPKAGRHC corresponding to 15 to 24 position
on AT1 receptor; RMHLRQYELL corresponding to
C-terminal position 385 to 394 on Gs;
KNNLKDCGLF corresponding to C-terminal common positions 345 to 154 and
346 to 355 on Gi1 and
Gi2; and QLNLKEYNLV corresponding to
C-terminal position on Gq/11. The
AT1 antibodies do not cross-react with
AT2 receptors. Similarly, the specificity of G
protein antibodies was confirmed with the lysates from separate
cultures of bacteria transformed with cDNA for various G protein
-subunits.
Data Analysis
The values were presented as mean±SEM and subjected to
2-way ANOVA for concentration response curves; 1-way ANOVA was used for
2 variables and for t test for the single concentration
responses. A value of P<0.05 was considered statistically
significant.
Chemicals
Bromocriptine was a gift from Sandoz Pharmaceuticals (E Nanover,
NJ). Domperidone was purchased from Research Biochemicals Intl.
Forskolin was purchased from Sigma Chemical Co. The kit for cAMP assay
was purchased from DuPont NEN. [3H]-Ang II was
purchased from Amersham. The kit for Western blot analysis was
purchased from Alpha Diagnostic Intl. Other chemicals for
various buffers were of the highest purity available and were purchased
either from Sigma or Fisher Scientific Co. The antibodies for
AT1 receptors and G proteins were purchased from
Santa Cruz Biotechnology, Inc and Calbiochem-Novabiochem,
respectively.
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Results |
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Effect of Bromocriptine Pretreatment on Ang II–Induced Stimulation of Na,K-ATPase Activity
Ang II produced a concentration-dependent (10-13 to 10-9 mol/L) stimulation in Na,K-ATPase activity. The maximal stimulation was observed at 10 pmol/L of Ang II (Figure 1
). Pretreatment of the tubules with
1 µmol/L bromocriptine for 30 minutes abolished the stimulatory
effect of Ang II (Figure 1). Domperidone (1 µmol/L), a
D2-like receptor antagonist,
prevented the effect of bromocriptine on Ang II response (Figure 1),
suggesting involvement of the D2-like receptors.
Bromocriptine alone did not influence Na,K-ATPase activity after the
total incubation time of 60 minutes (30 minutes of pretreatment and 30
minutes of further incubation with Ang II). The basal values of
Na,K-ATPase activities in control and bromocriptine-pretreated tubules
were 230±12 and 239±19 nmol Pi/mg protein per
minute, respectively. Simultaneous addition of
bromocriptine (1 µmol/L) and Ang II (10 pmol/L,
ECmax) to the tubules and incubation (for 30
minutes) stimulated Na,K-ATPase activity in a way similar to the
stimulation produced by 10 pmol/L of Ang II alone (data not shown).
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Effect of Bromocriptine Pretreatment on Ang II–Mediated Inhibition
of cAMP
Ang II (10 pmol/L) produced significant inhibition in cAMP
accumulation stimulated by 1 µmol/L forskolin (Figure 2). Bromocriptine (1 µmol/L)
pretreatment for 30 minutes completely prevented the
inhibitory effect of angiotensin on cAMP
accumulation (Figure 2). Bromocriptine alone over an incubation period
of 60 minutes did not significantly affect the basal cAMP level (Figure 2, open columns).
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Effect of Incubation Time on Bromocriptine-Mediated Inhibition of
cAMP Accumulation and Stimulation of Na,K-ATPase Activity
Bromocriptine had no effect on Na,K-ATPase activity or on cAMP
levels after an incubation period of 60 minutes (Figures 1
and 2). To
investigate the effect of incubation time, we incubated the proximal
tubules with bromocriptine (1 µmol/L) for varying periods (5 to
60 minutes), and the inhibition in the levels of cAMP accumulation and
the stimulation of Na,K-ATPase activity were measured. Figure 3 shows that the inhibition of cAMP
accumulation is maximal at 20 minutes of incubation, and it falls
dramatically at 30 minutes (>10%) with no inhibition at 60 minutes of
incubation. The stimulation of Na,K-ATPase activity has a similar
pattern. However, the maximal stimulation of Na,K-ATPase activity by
bromocriptine is at 30 minutes and falls sharply at 40 minutes
(>10%); negligible stimulation occurs at 50 and 60 minutes of
incubation.
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Effect of Bromocriptine Pretreatment on [3H]-Ang II
Binding and Quantity of AT1 Receptor
In this set of experiments, we chose a concentration of
10 to 12 nmol/L [3H]-Ang II, which has been
reported as its Kd at
AT1 receptors.14 Figure 4A shows that bromocriptine treatment
produced an 65% decrease in specific binding of
[3H]-Ang II (control 745±77 versus treated
264±24 fmol/mg protein) in proximal tubular membranes. The reduced Ang
II binding was also confirmed by Western blot analysis of
AT1 receptor using specific antibody. We detected
1 major band of 49 kDa and another minor band of 55 kDa (Figure 4B).
The density of the 49-kDa band was reduced by 50% in the membranes of
bromocriptine-treated proximal tubules. The density of the minor 55-kDa
band was similar in the control and the treated tubules (Figure 4B).
The 49-kDa protein represents glycosylated
AT1 receptor.22
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Quantification of G Proteins
Prolonged incubation of tissues/cells with receptor agonists may
lead to an alteration in the levels of G proteins and signaling systems
and may alter the receptor function. Because the incubation of proximal
tubules with bromocriptine for 60 minutes abolished its own effects on
both Na,K-ATPase activity and cAMP and also abolished the effects of
Ang II, the levels of G proteins were measured by Western blot
analysis in the proximal tubules treated with bromocriptine.
Figure 5 shows that 60 minutes of
incubation with bromocriptine increased the amount of
Gs by 2-fold (in both
GsShort and GsLong) and
decreased Gi1 and
Gi2. Gs and
Gi regulate adenylyl cyclase in a stimulatory and
inhibitory manner, respectively. Another protein,
Gq/11, which does not regulate adenylyl
cyclase but is present in the proximal tubules, was also measured
as a control. The amount of Gq/11 was not
altered in the proximal tubules incubated with bromocriptine compared
with control (Figure 5).
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Discussion |
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Dopamine and Ang II are 2 important regulators of sodium and water absorption in the kidney.1 2 During salt depletion, Ang II production and AT1 receptor expression increase in the proximal tubules, which subsequently causes an increased reabsorption of sodium and water.23 24 Conversely, sodium loading causes increased production of dopamine that, through the activation of D1-like dopamine receptors, promotes renal sodium and water excretion.25 It has been shown that dopamine can downregulate sodium uptake in response to Ang II in renal brush border membrane vesicles.14 Preactivation of D1-like receptors decreases expression of the AT1 receptors in the proximal tubules, possibly due to increased production of cAMP.15 The present study, which was conducted to examine the interaction between D2-like receptors and Ang II, shows that bromocriptine, a D2-like receptor agonist, downregulates Ang II binding sites and causes imbalance in the Gs/Gi proteins. This phenomenon may contribute to the abolished response of Ang II on the stimulation of Na,K-ATPase activity and the inhibitory effect on cAMP accumulation in the proximal tubules treated with bromocriptine.
In contrast to the role of the D1-like receptors,
the physiological role of
D2-like receptors is not yet well defined in the
kidney. However, the activation of D2-like
receptors has been proposed to synergize the effect of
D1-like receptors on Na,K-ATPase activity in the
proximal tubules,26 to inhibit
norepinephrine release from postganglionic sympathetic
nerves,27 and to produce antidiuretic
effects.28 Recently, we have shown that the
activation of D2-like receptors stimulated
Na,K-ATPase activity and inhibited cAMP accumulation in the proximal
tubules.17 These effects of bromocriptine, as
observed in this study, disappear after 40 minutes of incubation of
the proximal tubules with the agonist, which suggests the existence of
some regulatory mechanisms related to prolonged activation of
D2-like receptors. Such mechanisms may include
desensitization or internalization of the D2-like
receptor. In the present study, we found that such a regulation of
D2-like receptors by pretreatment of proximal
tubules with bromocriptine also abolished the stimulatory effect of Ang
II on Na,K-ATPase activity and the inhibitory effect on
cAMP accumulation. Furthermore, we found a decrease in Ang II binding
sites, a 2-fold increase in the amount of Gs
protein, and a decrease in Gi proteins in
bromocriptine-treated tubules, which may have contributed to the
failure of Ang II to stimulate Na,K-ATPase activity. The responses of
Ang II and bromocriptine on Na,K-ATPase activity share at least 1
common signaling pathway, ie, pertussis toxin–sensitive G protein
(likely Gi) linked inhibition of
cAMP.17 Adenylyl cyclase/cAMP is regulated by
Gs and Gi proteins in a
stimulatory and inhibitory manner. An imbalance in the
amount of Gs and Gi
proteins may alter regulation of the adenylyl cyclase pathway. It is
possible that prolonged activation of D2-like
receptors by bromocriptine decreased Gi and
increased Gs to compensate for the
inhibitory pathway. Because AT1
receptors are coupled to Gi, a decrease in the
levels of Gi and increased opposing basal tone of
Gs might have affected the response of Ang II.
Alterations in the levels of G proteins have been shown in
tissues/cells exposed to receptor agonist and in
pathophysiological conditions such as hypertension
and aging.29 30 31 32 For example, coronary
arteries exposed to A2 adenosine receptor
agonist produced a decrease in Gs and an increase
in Gi proteins.29 On the
other hand, A1 adenosine receptor agonist
exposure produced an increase in Gs and a
decrease in Gi proteins.30
Such alterations in the levels of G proteins have been suggested to
contribute to a change in the response not only of the receptors with
which the agonist interacts but also of those receptors that are linked
to these proteins. Such a phenomenon is referred to as heterologous
desensitization.
Bromocriptine treatment of the proximal tubules also led to a reduction in Ang II binding sites. In an earlier study, both D1-like and D2-like agonists were shown to decrease Ang II binding sites without causing a change in the affinity and without reducing the stimulatory effects of Ang II on phospholipase A2 and Na uptake by border brush membrane vesicles.14 On the basis of the earlier study,14 we propose that decrease in the Ang II receptor binding was not associated with any changes in the affinity. The reduction in [3H]-Ang II binding in the bromocriptine-treated tubules is further supported by Western blot analysis. Immunodetectable quantity of AT1 receptors is reduced in the proximal tubules treated with bromocriptine compared with the controls. The decrease in AT1 receptors by bromocriptine treatment may be because of (1) increased degradation of the receptor, (2) decreased synthesis of the receptor protein, or (3) both of these factors as contributors to this phenomenon. In another study, dopamine has been proposed to decrease AT1 receptor expression in the proximal tubule cells, possibly due to a D1-like receptor–mediated increase in cellular levels of cAMP.15 The mechanism by which D2-like receptor activation causes a decrease in Ang II binding sites and AT1 receptors is not known. However, the regulatory mechanism of the D2 receptor (a member of the D2-like dopamine receptor family) and its signaling pathway have been studied in the transfected cell lines.33 Quinpirole (1 µmol/L), a D2-like dopamine receptor agonist, produced inhibition in forskolin-stimulated cAMP,32 as we have found in the present study performed in the proximal tubules. Prolonged exposure of cells with quinpirole caused desensitization of the D2-receptor and sensitization of adenylyl cyclase, leading to higher basal cAMP in the agonist-treated cells.33 Although we did not detect significantly higher basal levels of cAMP in bromocriptine-treated proximal tubules, it is possible that a small increase in cAMP levels (15% to 20%) caused by prolonged exposure to bromocriptine may have contributed to a decrease in Ang II binding sites. The increase in cellular cAMP levels produced by dopamine (through the activation of D1-like receptors) has been implicated as the mechanism by which D1-like receptors regulate the AT1 receptors.15 On the basis of the above explanation, it may be speculated that both D1-like and D2-like receptor agonists decrease AT1 receptors partly by a similar mechanism, despite the fact that D1-like and D2-like receptors are linked to adenylyl cyclase in an opposing (stimulatory and inhibitory, respectively) manner. Furthermore, it is suggested that regulation of AT1 receptors may be linked with the changes in the G proteins. It is possible that the small increase in cAMP due to prolonged incubation with bromocriptine, which is implicated in the reduction of AT1 receptors, may be the result of increased Gs and decreased Gi proteins.
The regulation of the Ang II response by the D2-like receptors may be important under pathophysiological conditions. Recently, knockout of the D3 receptor, a member of the D2-like dopamine receptor family, increased renin-angiotensin activity and caused hypertension in mice, a condition that was reversed by the infusion of AT1 receptor antagonist losartan.34 This suggested that D2-like receptors play a role in keeping the low tone of the renin-angiotensin system in the kidney. The D1-like receptor that mediates natriuresis and diuresis is known to be defective in the proximal tubules of human primary hypertension and hypertensive animal models.20 35 36 Under such a pathophysiological condition, the D1-like receptor may not be able to antagonize the effects of Ang II as observed in normal animal models and in isolated proximal tubular preparations.13 14 15 It remains to be investigated whether prolonged administration of D2-like agonist can reduce the activity of Ang II by regulating the AT1 receptor/signaling pathway and promote sodium excretion in hypertensive animals, a response that may not be achieved by D1-like agonist because of a defect in D1-like receptor/signaling system.
In summary, the present study has demonstrated that prior treatment of proximal tubules with bromocriptine abolished Ang II stimulation of Na,K-ATPase activity and inhibition of cAMP accumulation. The bromocriptine treatment of the proximal tubules was accompanied by a decrease in AT1 receptors and alterations in G proteins, which may have contributed to the failure of Ang II to stimulate Na,K-ATPase activity and inhibit cAMP accumulation. We propose that heterologous desensitization of D2-like receptors may be an underlying mechanism responsible for affecting the Ang II response on the sodium pump. The physiological significance of the D2-like receptor regulation of the Ang II response in normal and disease states remains to be determined.
Received April 20, 1998; first decision May 6, 1998; accepted July 29, 1998.
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