Division of Nephrology and Hypertension and Center for Hypertension and Renal Disease Research, Georgetown University Medical Center, Washington, DC 20007
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ABSTRACT |
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A TP receptor (TP-R) mimetic causes
salt-sensitive hypertension and renal afferent arteriolar
vasoconstriction. TP-Rs mediate effects of ANG II on renal vascular
resistance and drinking. Therefore, we investigated the hypothesis that
thromboxane A2 synthase (TxA2-S) and/or TP-R
expression is regulated by salt and/or ANG II. Rats (n = 6) received high-salt (HS) or low-salt (LS) diets. Additional HS-diet
rats received ANG II while other HS- and LS-diet rats received the
AT1 receptor (AT1-R) antagonist
losartan. Excretion of thromboxane B2 by conscious
rats was increased with the HS diet compared with the LS diet (126 ± 10 vs. 48 ± 5 pmol/24 h, respectively; P < 0.01). The mRNA abundance for TP-Rs (relative to -actin) in
the kidney cortex was enhanced 30% by the HS diet (P < 0.001) and was reduced 50% by the addition of ANG II
(P < 0.001). However, during losartan administration,
the effects of salt were reversed; mRNA more than doubled during the LS
diet (P < 0.001). Similarly, the mRNA abundance for
TP-Rs in the brain stem was reduced by 50% with the addition of ANG II
(P < 0.001) and during losartan administration was
almost doubled by the LS diet (P < 0.001). The mRNA
abundance for TxA2-S in the kidney cortex also was
increased many times with the HS diet (P < 0.001). In
contrast, the mRNA for TxA2-S in the brain was unaffected
by salt. ANG II did not affect TxA2-S at either site.
During losartan administration, TxA2-S increased modestly
in the brain stem with the LS diet. mRNA abundance for TP-Rs in the
kidney cortex and brain stem is suppressed by ANG II acting on
AT1-Rs. In the absence of AT1-Rs,
expression of TP-Rs at both sites is enhanced by LS intake. In
contrast, ANG II does not affect the mRNA abundance for
TxA2-S. Expression of TxA2-S is enhanced by HS
intake in the kidney cortex but by LS intake in the brain stem only
during losartan administration. Thus TP-Rs are strongly dependent on
ANG II acting on AT1-Rs, whereas TxA2-S is
regulated differentially in the kidney cortex and brain stem by salt intake.
thromboxane A2; prostaglandins; angiotensin II; losartan; angiotensin receptor blocker; thromboxane prostanoid receptor
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INTRODUCTION |
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THROMBOXANE
A2 (TXA2) IS
GENERATED from PGH2 by TxA2 synthase
(TxA2-S). TxA2-S is expressed in the kidney
(53). TxA2, PGH2, and
isoprostanes, such as 8-iso-PGF2, and stable mimetics, such as U-46619, are agonists for the TP receptor (TP-R) (14, 17). TP-Rs are expressed in the blood vessels and in kidney microvessels, glomeruli, mesangial cells, thick ascending limbs (TALs)
of the loops of Henle, and collecting ducts (1, 10, 11,
48).
Several lines of evidence suggest that TxA2-S and TP-Rs in the kidney are regulated by salt intake or ANG II. Thus hypertension in response to a prolonged infusion of U-46619 is enhanced by high-salt (HS) intake (55). U-46619 enhances the sympathetic nervous system of conscious rats (13) and the vasoconstrictive tubuloglomerular feedback (TGF) response of anesthetized rats. Both of these effects are enhanced by an HS diet (56). Moreover, the effects of U-46619 on TGF correlate with the abundance of the mRNA for TP-Rs in kidney and glomeruli of rats on different salt intakes. Thus the kidney is sensitive to TP-R activation, and this response is salt dependent. However, effects of salt on TxA2-S expression or on thromboxane B2 (TxB2) excretion are not clear.
The brain also generates TxA2 (6, 8, 44-47) and expresses TP-Rs (12, 34) on glial cells and astrocytes (12, 18, 34, 35). The intracerebroventricular administration of U-46619 increases blood pressure. This pathway also is sensitive to salt. Thus the increase in blood pressure with intracerebroventricular U-46619 is enhanced by HS intake (12). The drinking response to central ANG II is blunted by intracerebroventricular injection of a TP-R antagonist (19). A TP-R mimetic and ANG II, when given into the brain, synergize to promote drinking (19). Thus the brain-TP-R pathway apparently interacts with salt intake and ANG II, but the mechanism is unclear.
Vasoconstrictor PGs enhance many of the effects of ANG II. Thus blockade of TP-Rs, and in some studies blockade of TxA2-S, blunts or prevents the pressor response to infused ANG II (32, 33, 62), the development of renovascular hypertension in the two-kidney, one-clip Goldblatt or aortic coarctation models of renovascular hypertension in the rat (23, 59, 60), the increase in renal vascular resistance during ANG II infusion (24, 31, 62) and the dipsogenic response to intracerebroventricular ANG II infusion (19). These data implicate TxA2-S and/or TP-Rs in the renal and central nervous system actions of ANG II. Therefore, we investigated the hypothesis that dietary salt intake or ANG II regulate the mRNA abundance for TP-Rs and TxA2-S in the kidney cortex and brain stem.
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METHODS |
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Studies were undertaken on male Sprague-Dawley rats weighing 200-250 g. Animals were habituated in their cages to a standard rat chow (Na+ content 0.3 g/100 g; Ralston Purina) for 5 days before randomization. Thereafter, all rats were fed a regulated diet with identical composition except for the NaCl (Teklad, Madison, WI). The Na+ content of the HS diet was 3 g/100 g, and for the LS diet it was 0.03 g/100 g. The LS diet is sufficient for normal growth over an 8- to 10-day period. Rats were studied after 6 days on each protocol.
Protocols. Rats were studied according to the following protocols: 1) series A; group 1, HS intake (n = 6); group 2, LS intake (n = 6); and group 3, HS+ANG II intake (n = 6); and 2) series B; group 4, HS+losartan intake (n = 6); and group 5, LS+losartan intake (n = 6). Rats in series A and B were analyzed separately.
Before starting the 6 days of a regulated diet, animals in group 3 were anesthetized with pentobarbital sodium (50 mg/kg ip; Abbott Laboratories, North Chicago, IL) and fitted with a subcutaneous osmotic minipump (Alza, Palo Alto, CA) to deliver ANG II at 200 ng · kgExcretion of TxB2.
Rats were studied on day 6 of LS or HS diets. They were
accommodated for 1 day to metabolism cages, and for the next 24 h a urine sample was collected from the cage. Urine was collected into
containers with streptomycin (2,000 IU), penicillin G (2,000 IU), and
amphotericin B (5 µg) to prevent microbial growth. It was
centrifuged, separated from sediment, and stored at 70°C until
analyzed for TxB2. These rats were separate from those used for mRNA studies.
Extraction and analysis of mRNA.
For preparation of the kidney (56) and brain
(12), groups of rats were anesthetized on day 6 of the protocol with thiobarbital (Inactin, 100 mg/kg ip; Research
Biochemicals International, Natick, MA). The chest was opened, and the
left ventricle was punctured to flush the organs with ice-cold 0.154 NaCl. The entire brain stem (dissected free from the cerebellum,
midbrain, and cortex) and one kidney were removed, cleared of
connective tissue, and placed in ice-cold saline solution. The kidney
was cut longitudinally and a segment of cortex was removed. Total RNA
was extracted by using RNA ATAT-60 (Tel-test B, Friendswood, TX). The
mRNA was reverse transcribed with oligo(dT)16 as the primer
and murine leukemia virus RT by using an RNA PCR kit (PerkinElmer,
Branchburg, NJ). The primers used for PCR for the TP-R gene product
were selected from the published cDNA sequences of the rat TP-R
(GenBank accession no. D32080) (1). For
TxA2-S, the sense was 5'-TTCCTGCAGATGGTGCTGGATG-3' and the
antisense was 5'-AGGTATGTGATGAAGGAGAGCG-3' (235 bp) and TxA2-S (64) (GenBank accession no. D31798)
(49) as described previously (12). For the
TP-R, the sense was 5'- TGGACTGGCGTGCCACTGAT-3' and the antisense was
5'-AGCAAGGGCATCCAACACACCGTG-3' (502 bp). The primers for the TP-R were
selected to amplify the - and
-isoforms of the receptor
(30).
-Actin was selected as the "housekeeper gene"
for comparison, because
-actin mRNA abundance in the rat kidney is
independent of salt intake (56). The sense primer was
5'-GATCAAGATCATTGCTCCTC-3', and the antisense was
5'-TGTACAATCAAAGTCCTCAG-3' (426 bp). We detected no differences in
-actin expression in the kidneys or brain stem in the different
groups used in these protocols. Therefore, the amounts of TP-R and
TxA2-S cDNAs were normalized by the amounts of
-actin
cDNA. The reaction mixture contained 50 pmol of each primer, 1.25 mM
deoxynucleotide mixture, 2.5 µl Taq DNA polymerase, 10 mM
Tris (pH 10), 50 mM KCl, and 1.5 mM MgCl2 and was carried
out by the following protocol. After an initial melting temperature of
94°C for 4 min, there were 30 s of denaturation at 94°C,
45 s of annealing at 60°C, and 45 s of extension at 72°C
for 7 min. The PCR product was analyzed on a 1.5% agarose gel stained
with ethidium bromide and visualized under ultraviolet light. The size
of the products was compared with rat kidney cDNA probes for TP-Rs
(1) and TxA2-S (49), kindly
provided by Dr. Kazu Takeuchi (Tokohu University, Sendai, Japan). To
verify authenticity of the PCR products, amplified TP-R and
TxA2-S cDNAs from the rat kidney cortex and brain stem were purified with Microcon (Amicon, Beverly, MA) and sequenced with an AmpliTaq cycle sequencing kit (PerkinElmer).
Statistical analysis. The data were subjected to ANOVA to assess the effects of salt intake (group 1 vs. 2; series A) and ANG II (group 1 vs. 3; series A) and of salt intake during losartan administration (group 4 vs. 5; series B). Data are presented as means ± SE.
The studies were designed to test two a priori hypotheses. First, the expression of mRNA for TxA2-S or TP-Rs could be stimulated by ANG II independently of salt intake. This was refuted if there was no significant difference in mRNA abundance in a comparison of HS intake with HS+ANG II intake. Second, the expression of mRNA for TxA2-S or TP-Rs could be stimulated by salt intake independently of AT1 receptors (AT1-Rs). This was refuted if there was no significant difference between LS+losartan intake and HS+losartan intake. ![]() |
RESULTS |
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The 24-h excretion of TxB2 by conscious rats
is shown in Fig. 1. It is apparent that
excretion is increased significantly by 6 days of HS intake compared
with LS intake.
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The mRNA abundance for TP-Rs (relative to -actin) extracted from the
kidney cortex and brain stem during HS, LS, and HS+ANG II intake are
shown in Fig. 2. For the kidney but not
the brain, HS intake enhanced the mRNA for TP-Rs by 30%
(P < 0.001). For both the kidney and the brain, the
abundance of TP-Rs during HS intake was reduced by ~50% by ANG II
infusion (P < 0.001). We conclude that ANG II infusion
inhibits mRNA for TP-Rs in the kidney cortex and brain stem
independently of salt intake.
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During losartan administration, LS intake led to a large increase in
the mRNA for TP-Rs in the kidney cortex (2-fold) and brain stem (60%)
(Fig. 3). Thus salt restriction
stimulates TP-R expression in the kidney and brain independently of
AT1-Rs.
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The mRNA abundance for TxA2-S (relative to -actin) in
the kidney cortex and brain stem during HS, LS, and HS+ANG II intake is
shown in Fig. 4. The TxA2-S
abundance in the kidney was increased >20-fold during HS intake,
whereas the abundance in the brain was not changed significantly.
Unlike TP-Rs, there were no effects of ANG II during HS intake.
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During losartan administration, there was a similar effect of salt
intake on TxA2-S in the kidney (Fig.
5) as seen in the absence of losartan
(Fig. 4). However, during losartan administration there was an increase
in mRNA for TxA2-S in the brain stem during LS intake of
60%. We conclude that salt intake has divergent effects on
TxA2-S expression in the kidney and brain. Salt loading
stimulates expression in the kidney, and salt restriction stimulates
expression in the brain. These effects are largely independent of ANG
II and AT1-Rs.
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DISCUSSION |
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Our laboratory found previously that HS intake enhances mRNA abundance for TP-Rs in the kidney cortex and glomeruli (56). This was confirmed in the present study. The main new findings are that this effect of HS intake to increase mRNA abundance for TP-Rs is specific for the kidney because it is not found in the brain stem and is dependent on ANG II and AT1-Rs at both sites. Remarkably, during losartan administration, the increased TP-R expression in the kidneys seen during HS intake is reversed, and in both the kidney and the brain, TP-R expression is increased substantially by salt restriction when the effects of AT1-Rs are prevented by losartan. These data demonstrate that the prominent effect on TP-R expression in these protocols is suppression by ANG II acting on AT1-Rs. This action of ANG II apparently conceals an effect of salt restriction to enhance expression that is seen only during AT1-R blockade. Because ANG II levels diminish during HS intake and ANG II suppresses the expression of TP-Rs, the increase in TP-Rs in the kidneys with HS intake may be ascribed to a loss of the inhibitory effect of ANG II acting on AT1-Rs. Similar to TP-Rs, the mRNA abundance for TxA2-S also increases with HS intake in the kidney, although it is not changed in the brain. However, ANG II does not change the expression of TxA2-S in the kidney or brain. Moreover, the increase in TxA2-S with HS intake in the kidney and with LS intake in the brain persists during losartan administration. We conclude that the major determinant of TxA2-S expression is salt intake independent of ANG II and AT1-Rs. These data indicate the quite distinct effects of ANG II on the regulation of the mRNAs for TP-Rs and TxA2-S.
Rat glomeruli and mesangial cells contain high-affinity binding sites for TP-R ligands (10, 14). The distribution of TP-R protein within the kidney has been studied by immunocytochemistry. Receptors are located on arterial walls, microvessels, glomeruli, proximal tubules, TALs, distal tubules, and collecting ducts (4, 48). In situ hybridization studies have located the mRNA for TP-Rs in glomeruli, afferent and efferent arterioles, the luminal aspects of the TALs, macula densa cells, collecting ducts (1), and the renal medulla (27). Receptor-mediated contractile responses to TP-R activation have been shown in isolated glomerular mesangial cells and renal afferent arterioles (16, 25, 28, 43). A thromboxane mimetic enhances NaCl reabsorption in the loop of Henle and enhances the TGF responses (58). These data suggest that TP-Rs are distributed to renal microvessels, glomeruli, macula densa cells, and tubules of the kidney. TP-Rs also are expressed in the brain (3), where they are distributed to glial cells and astrocytes (12, 18, 34).
We considered two explanations for the reduction of TP-R expression by
ANG II. First, this could represent ligand-associated receptor
downregulation (39). ANG II stimulates phopholipases that
substantially enhance PG formation in the kidney (26,
29). ANG II infusion increases renal excretion of
TxB2, implying enhanced renal TxA2 generation
(26). Indeed, blockade of TxA2-S or TP-Rs blunts the renal vasoconstriction with prolonged ANG II infusion (31, 62). An increase in vasoconstriction has been
ascribed to PGH2, which also activates TP-Rs
(22). Moreover, ANG II leads to oxidative stress and an
enhanced excretion of 8-iso-PGF2 (41, 42).
Thus all the identified ligands of the TP-R are generated in response
to ANG II infusion. Ligand-associated downregulation of TP-Rs could
account for the reduced expression of TP-Rs in the kidney during ANG II
infusion and the enhancement during AT1-R blockade with losartan.
A second possible explanation derives from the evidence that losartan also blocks TP-Rs (7, 21). Therefore, the losartan-induced increase in mRNA for TP-Rs may represent upregulation of the receptor during pharmacological blockade. It is not clear how this could explain the large effects of salt intake on TP-R expression during losartan administration.
The protein for TxA2-S is expressed in renal microvessels, interstitial fibroblasts, and macrophages (36, 40), and in the distal nephron of the kidney (37). Isolated glomeruli and glomerular mesangial cells and podocytes release TxB2 and therefore presumably express TxA2-S (29). Microdissected nephron segments also release TxB2. The largest sites for release are glomeruli, TALs, and collecting ducts (2). Thus TxA2 can be widely synthesized in the kidney. In the brain, TxA2 is synthesized predominantly in glia (44, 45). Very large quantities of TxB2 are released from the brain in response to hypoperfusion or trauma (6, 8, 46). However, we are not aware that the regulation of TxA2-S in the kidney or brain has been studied directly.
The cause for the salt-dependent, but ANG II- and AT1-R-independent, increase in mRNA abundance for TxA2-S in the kidney is not clear. This is analogous to the salt-dependent, but ANG II- and AT1-R-independent, expression of mRNA and protein for nitric oxide synthase type I in the kidney cortex and macula densa cells (51, 52). It demonstrates that the kidney contains potentially unique mechanisms that would provide it with the potential to enhance the generation of nitric oxide in the juxtaglomerular apparatus during LS intake and of TxA2 during HS intake. This could contribute to kidney-specific regulation of vascular tone during changes in salt intake. The large increase in TxA2-S mRNA expression in the kidney cortex observed during HS intake may explain the finding that renal TxB2 excretion (and hence TxA2 generation in the body) increases two- to threefold during HS intake compared with LS intake (Fig. 1).
These results suggest that during LS intake there is normally a powerful stimulus for expression of TP-Rs in kidney cortex and brain stem. However, an associated increase in ANG II, acting on AT1-Rs, feeds back to reverse the effect of salt in the kidney and prevent the effect in the brain stem. This is analogous to studies of cyclooxygenase-2 (COX-2) in the kidney cortex. COX-2 expression is enhanced during LS intake; this effect is exaggerated by blockade of ANG II generation with an angiotensin-converting enzyme inhibitor (15). This has led to the hypothesis that ANG II feeds back to blunt salt-induced changes in COX-2 expression. The major difference in the renal regulation of TP-Rs and COX-2 appears to be in the relative importance of ANG II, which is predominant for TP-Rs, resulting in an actual reversal of the direct effects of salt on TP-R expression in the kidney.
A limitation of our study is the use of mRNA to assess receptor or enzyme function. However, there is a correlation among several findings with mRNA expression in the present series and functional data. Thus the 10-fold increase in TxA2-S mRNA expression in the kidney with HS intake (Fig. 4) is mirrored by a two- to threefold increase in TxB2 excretion (Fig. 1). The increase in TP-R mRNA expression in the kidney with HS intake (Fig. 2) is mirrored by the increased responsiveness of the afferent arteriole to U-46619 microperfused into the renal interstitium during HS intake (56) and the greater increase in blood pressure (55) and sympathetic nervous system activity (13) in response to prolonged infusion of U-46619 during HS intake. The finding that the expression of TP-R mRNA in the brain stem is downregulated by ANG II (Fig. 2) may be relevant to the interaction between ANG II and TP-Rs in the brain in the control of drinking (19).
Perspectives. There are several implications of our study. First, the upregulation of TP-Rs and TxA2-S in the kidney cortex during HS intake may contribute to the prohypertensive role of vasoconstrictor PGs in salt-dependent forms of hypertension, such as ANG II-salt hypertension (32), DOCA-salt (20, 38), or the Dahl salt-sensitive rat (50, 54, 63). Our laboratory had shown previously that hypertonic NaCl infusion selectively increases the release of TxB2 into urine and renal lymph (61). An accompanying increase in afferent and efferent arteriolar resistance is blocked by inhibition of COX or TxA2-S (5). The present finding that HS intake enhances TxB2 excretion and enhances TP-Rs and TxA2-S in the kidney cortex suggests that salt loading could increase TxA2 generation and response to TP-R activation. Third, HS intake potentiates the increase in blood pressure that occurs during a prolonged infusion of a TP-R mimetic (55) and the increase in afferent arteriolar vasoconstriction during local microperfusion of a TP-R mimetic into the kidney (56). This correlates with an increase in the mRNA for TP-Rs in the kidney during salt loading. Therefore, these new findings that salt intake and/or ANG II regulates TP-R and TxA2-S mRNA expression in the kidney and brain likely have functional significance.
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ACKNOWLEDGEMENTS |
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We are grateful to Dr. Bo Peng for technical assistance and Sharon Clements for the preparation of this manuscript.
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FOOTNOTES |
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This work was supported by National Institutes of Health Grants DK-49870, DK-36079, and PO1-HL-68686-01 and funds from the George E. Schreiner Chair of Nephrology.
Address for reprint requests and other correspondence: C. S. Wilcox, Div. of Nephrology and Hypertension, Georgetown Univ. Medical Ctr., 3800 Reservoir Rd., NW PHC F6003, Washington, DC 20007 (E-mail: wilcoxch{at}georgetown.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.
10.1152/ajprenal.00256.2002
Received 16 July 2002; accepted in final form 5 November 2002.
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