Published online before print December 26, 2006, doi: 10.1161/01.HYP.0000254486.00883.3d
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(Hypertension. 2007;49:672.)
© 2007 American Heart Association, Inc.
Original Articles, Part 2 |
Reactive Oxygen Species–Dependent Hypertension in Dopamine D2 Receptor–Deficient Mice
From the Department of Pediatrics and Physiology and Biophysics, Georgetown University Medical Center, Washington, DC.
Correspondence to Ines Armando, Department of Pediatrics, Georgetown University Medical Center, 4000 Reservoir Rd, NW, Washington, DC 20057. E-mail ma383{at}georgetown.edu
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Abstract |
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Dysfunction of D2-like receptors has been reported in essential hypertension. Disruption of D2R in mice (D2–/–) results in high blood pressure, and several D2R polymorphisms are associated with decreased D2R expression. Because D2R agonists have antioxidant activity, we hypothesized that increased blood pressure in D2–/– is related to increased oxidative stress. D2–/– mice had increased urinary excretion of 8-isoprostane, a parameter of oxidative stress; increased activity of reduced nicotinamide-adenine dinucleotide phosphate oxidase in renal cortex; increased expression of the reduced nicotinamide-adenine dinucleotide phosphate oxidase subunits Nox1, Nox2, and Nox4; and decreased expression of the antioxidant enzyme heme-oxygenase-2 in the kidneys, suggesting that regulation of reactive oxygen species (ROS) production by D2R involves both pro-oxidant and antioxidant systems. Apocynin, a reduced nicotinamide-adenine dinucleotide phosphate oxidase inhibitor, or hemin, an inducer of heme oxigenase-1, normalized the blood pressure in D2–/– mice. Because D2Rs in the adrenal gland are implicated in aldosterone regulation, we evaluated whether alterations in aldosterone secretion contribute to ROS production in this model. Urinary aldosterone was increased in D2–/– mice and its response to a high-sodium diet was impaired. Spirolactone normalized the blood pressure in D2–/– mice and the renal expression of Nox1 and Nox4, indicating that the increased blood pressure and ROS production are, in part, mediated by impaired aldosterone regulation. However, spironolactone did not normalize the excretion of 8-isoprostane and had no effect on expression of Nox2 or heme-oxygenase-2. Our results show that the D2R is involved in the regulation of ROS production and that, by direct and indirect mechanisms, altered D2R function may result in ROS-dependent hypertension.
Key Words: aldosterone • mineralocorticoids • genetics-animal models • hypertension, kidney
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Introduction |
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Dopamine has an important role in the regulation of systemic blood pressure.1,2 It affects fluid and electrolyte balance by its actions on renal hemodynamics and epithelial ion transport and by regulation of the secretion/metabolism of hormones and humoral agents1 and exerts its actions via 2 families of G protein–coupled receptors: D1-like receptors (D1R and D5R) and D2-like receptors (D2R, D3R, and D4R).1–3 There is abundant evidence that an intact dopaminergic system is necessary to maintain normal blood pressure and that genetic hypertension is associated with alterations in dopamine production and receptor function.1–4 In humans and rodents, some dopamine receptor genes and their regulators are in loci linked to hypertension.3,5 The natriuretic effect of D1-like agonists is impaired in genetically hypertensive rats3,4 and in human essential hypertension.3,4 Alterations in D2-like receptor function have also been reported in hypertension.1,2 Loci in chromosome 11, where the D2R gene is located, are linked to hypertension.5,6 A polymorphism in exon 6 of the D2R gene is associated with elevated blood pressure,7 and a TaqI polymorphism is associated with human essential hypertension.8 Several D2R polymorphisms are associated with decreased D2R expression9,10 and affect D2R mRNA stability and synthesis of the receptor.11 The disruption of any of the dopamine receptor genes in mice produces dopamine receptor subtype–specific hypertension.3,12–14 Specifically, disruption of the D2R gene increases systolic and diastolic blood pressure in mice but does not affect the ability to excrete an acute sodium load.13 Another D2R-deficient mouse model has been shown to be salt sensitive.15
Reactive oxygen species (ROS) encompass a series of oxygen intermediates that include the free radical superoxide anion.16 Increased production, decreased scavenging, or metabolism of ROS results in oxidative stress, an important prohypertensive mechanism. Generation of ROS is increased in human essential hypertension and animal models of genetic and experimental hypertension.14,16–18 Conversely, mouse models deficient in ROS-generating enzymes have lower blood pressure than their wild-type controls.19 Increased generation of ROS or ROS-dependent products has been demonstrated in kidneys of hypertensive animals.14,16,18 Increased renal superoxide anion production is associated with inactivation of NO, which influences afferent arteriolar tone, tubuloglomerular feedback responses, and sodium reabsorption,16 all important mechanisms in the long-term regulation of blood pressure.
Dopamine has contrasting effects on ROS production. At high concentrations, dopamine, D1-like receptors agonists,20 and excessive stimulation of D2-like receptors can increase ROS production. However, D1-like and D2-like receptors act as antioxidants at physiological concentrations of dopamine and low concentrations of their respective agonists.4,21–23 Low concentrations of dopamine, acting at D1R and D5R, decrease ROS in renal tubular and vascular smooth muscle cells21 and brain cortical cells.23 D5R–/– mice are hypertensive, in part, caused by increased systemic ROS production14 related to increased expression/activity of pro-oxidants and decreased expression/activity of antioxidants. D2R agonists have neuroprotective effects in experimental models24,25 and show free radical scavenging and antioxidant activity in vitro and in vivo.25,26 In vitro and in vivo studies have shown that the protective effects of D2R were eliminated when they were coadministered with D2R antagonists, indicating that D2R activation contributes to the neuroprotective effects.27,28
We asked the question whether D2R dysfunction results in increased ROS production that, in turn, may have a role in blood pressure regulation and focused our studies on the kidney. For this purpose, we studied in D2R gene–disrupted mice the urinary excretion of 8-isoprostane, a marker of oxidative stress, the renal expression and activity of pro-oxidant and antioxidant systems, and the effects of drugs that decrease ROS production. Because D2Rs in the adrenal gland have been reported to be involved in the regulation of aldosterone secretion, we also evaluated whether alterations in aldosterone secretion may contribute to ROS production in this model.
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Methods |
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D2 Receptor–Deficient Mice
The original F2 hybrid strain (129/SvXC57BL/6J, Oregon Health Sciences University) that contained the mutated D2R allele (D2–/–) was backcrossed to wild-type C57BL/6J for >5 generations and genotyped.13 Wild-type littermates (D2+/+) were used as controls. Mice were 6 to 8 months of age. All of the studies were approved by the Georgetown University Animal Care and Use Committee.
Blood Pressure Determination and Urine Collection
Systolic and diastolic blood pressures were measured (Cardiomax II, Instruments) from the aorta, via the femoral artery, under pentobarbital anesthesia (50 mg/kg IP). Blood pressures were recorded 1 hour after the induction of anesthesia, and the blood pressures were stable. The kidneys were harvested, frozen in isopentane at –30°C on dry ice, and stored at –80°C until studied. The mice were euthanatized (pentobarbital 100 mg/kg) at the conclusion of the study. Mice were housed in metabolic cages the day before blood pressure measurement for collection of 24-hour urine samples.
Blood pressure was also measured in conscious mice by telemetry. TA-PAC20 transmitters (Data Sciences International) were implanted into the carotid artery under isoflurane anesthesia, and blood pressures were measured 1 week after the surgery.12
Treatment With Apocynin
Apocynin (3 mg/kg per day, Sigma), a drug that inhibits reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase activity by impeding the assembly of the NADPH oxidase complex,14 was administered via osmotic mini-pumps (Alzet) for 10 days. The drug was dissolved (1.5 mg/100 µL in a mixture of DMSO/saline (final concentration of DMSO 12.5%). On day 10 of infusion, the mice were housed in metabolic cages for 24-hour urine collection. At the end of the urine collection period, mice were anesthetized, and blood pressure was measured as described above.
Treatment With Hemin
Hemin, an inducer of heme-oxygenase (HO)-1, was dissolved in chloroform (1 mg/50 µL) and diluted in saline to reach a final dose of 50 µmol/kg per 100 µL. Hemin or vehicle was administered intraperitoneally. Blood pressure was measured under anesthesia before and 24 hours after drug administration.
Treatment With Spironolactone
Spironolactone (20 mg/kg per day, Sigma), a competitive antagonist of the mineralocorticoid receptor, was administered via osmotic minipumps for 7 days. Minipumps were filled with spironolactone or vehicle (saline) and implanted under the skin. On day 7, 24-hour urine samples were collected in metabolic cages. Thereafter, mice were anesthetized for blood pressure measurement, and kidneys were harvested as described above.
Urine Measurements
Urinary aldosterone was determined by radioimmunoassay (Diagnostic Products Corporation) in 24-hour urine samples collected in mice on a normal salt diet (0.8% NaCl) and 1, 2, and 7 days after mice were fed a high-salt diet (4% NaCl). Urinary 8-isoprostane, an index of oxidative stress,16 was determined by enzyme immunoassay (Cayman Chemical Company). Values were corrected for urinary creatinine.
RNA Extraction and RT-PCR
Kidney samples were homogenized, and total RNA was extracted using the RNeasy RNA Extraction kit (Qiagen). Semiquantitative RT-PCR was carried out using Superscript III One-Step RT-PCR kit (Invitrogen) following the manufacturer’s protocol. Human ß-actin was used as the housekeeping gene. The primers used for determination of mRNA expression of the NADPH oxidase subunits p22phox, p40phox, p47phox, p67phox, Rac1, Rac2, Nox1, Nox2, and Nox4 and the HO isoforms HO-1 and HO-2 are listed in Table I (available in an online supplement at http://hyper.ahajournals.org). The products were resolved in 2% agarose gel and visualized using a digital gel documentation system (Alpha Innotech Corporation). Band densities were quantified using Scion software.
Immunoblotting
Mouse kidney homogenates were subjected to immunoblotting, as reported previously.12–14 The primary antibodies used were polyclonal anti-Nox1 (Santa Cruz Biotechnology), monoclonal anti Nox-2 (a kind gift of Dr M. T. Quinn, Department of Veterinary Molecular Biology, Montana State University, Bozeman, MT), monoclonal anti-HO-1 (Stressgen), polyclonal anti-HO-2 (Stressgen), polyclonal anti-actin (Sigma), and a Nox4 affinity-purified antibody developed and characterized in our laboratory (Figure I). The densitometry values were corrected by expression of ß-actin and are shown as percentage of the mean density of the control group.
Determination of NADPH Oxidase Activity
NADPH oxidase activity (light units per milligram of protein) was determined by measuring NADPH-induced chemiluminescence in the presence of lucigenin (5 µmol/L) and NADPH (100 µmol/L; ICN Biomedicals).14 The specificity of the NADPH-dependent superoxide anion production was verified by treatment with diphenylene iodinium (Sigma).
Statistical Analysis
Data are mean±SEM. One-way ANOVA followed by posthoc analysis using the Newman–Keuls multiple comparison test was used to assess the significant differences among groups. Comparisons between 2 groups used the Student t test. P<0.05 was considered statistically significant.
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Results |
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Blood Pressures in D2–/– Mice
Both systolic and diastolic blood pressures were significantly higher in anesthetized D2–/– than in D2+/+ (Figure II), confirming our previous findings in these mice.13 These results were further confirmed in conscious mice. Both systolic (Figure 1A) and diastolic (data not shown) blood pressures measured by telemetry were also significantly higher in D2–/– than in D2+/+. The decrease in systolic blood pressure occurring during the daytime in D2+/+ was not observed in D2–/– (Figure 1A).
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Excretion of 8-Isoprostane, Activity and Expression of NADPH Oxidase, and Expression of HO Isoforms
Urinary excretion of 8-isoprostane was increased in D2–/– compared with D2+/+ (Figure 1B). This effect was associated with increased NADPH oxidase activity in renal cortex of D2–/– in comparison with D2+/+ (Figure 1C). The increased NADPH oxidase activity in renal cortex of D2–/– was associated with increased expression of Nox isoforms (Figure 2A and 2B). The protein expressions of Nox1, Nox2, and Nox4 were increased by 45±8%, 89±10%, and 55±5%, respectively, compared with D2+/+ mice (Figure 2B). The increased protein expression of Nox isoform D2–/– mice was apparently the consequence of increased gene transcription, because we found that renal mRNA expressions of Nox1, Nox2, and Nox4 were increased by 30±3%, 14±1%, and 29±2%, respectively, in D2–/– (Figure 2A). The renal mRNA expressions of the other NADPH oxidase subunits (p22phox, p40phox, p47phox, p67phox, Rac1, and Rac2) were found to be similar in D2–/– and D2+/+ (Figure III). Increased oxidative stress in D2–/– was also associated with a decreased renal mRNA and protein expression of HO-2 but unaltered expression of HO-1 (Figure 2C and 2D).
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Excretion of Aldosterone Under Normal and High-Salt Diet
On a normal salt diet, urinary excretion of aldosterone was 
2-fold in D2–/– mice compared with D2+/+ (Figure 3A). After 2 days on a high-salt diet, aldosterone was lower, whereas after 7 days of a high-salt diet, urinary aldosterone was higher in D2–/– than in D2+/+, suggesting an alteration in the aldosterone response to increased sodium intake in D2–/– mice (Figure 3B).
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Effect of Apocynin
Treatment with apocynin decreased systolic blood pressure in anesthetized D2–/– so that they were no longer different from D2+/+ mice; apocynin had no effect in D2+/+ (D2–/–, 96±2; D2+/+, 96±1 mm Hg; Figure 4A and Figure II). Apocynin also decreased urinary excretion of 8-isoprostane in D2–/– to levels similar to those in D2+/+ (Figure 4B). The renal expression of Nox1 in D2–/– decreased to levels similar to those in D2+/+, the expression of Nox 2 remained increased to about the same levels as in untreated mice, and that of Nox4 was further increased by apocynin treatment (Figure 4C).
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Effect of Hemin
Twenty-four hours after administration of hemin, systolic blood pressure decreased in D2–/– to levels similar to those in D2+/+. Hemin had no significant effect on systolic blood pressure in D2+/+ (Figure 5). Vehicle treatment had no effect on blood pressure in either mouse strain.
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Effect of Spironolactone
Spironolactone decreased systolic (Figure 6A) and diastolic (data not shown) blood pressure in anesthetized D2–/– but had no significant hypotensive effect in D2+/+ mice. The urinary excretion of 8-isoprostane was not decreased by spironolactone in either mouse strain. In fact, urinary 8-isoprostane tended to be increased rather than decreased in D2+/+, although the increase was not statistically significant (Figure 6B). The renal expressions of Nox1 and Nox4 were decreased in D2–/– to levels similar to those in D2+/+ (Figure IV). However, the expression of Nox2 was not affected by spironolactone (Figure 6C). In contrast, the expression of HO-2 was slightly but not significantly decreased in D2–/– and significantly reduced in D2+/+ to 50% of the levels in vehicle-treated mice (Figure 6D). The expression of HO-1 was not affected in any of the groups by spironolactone (data not shown).
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Discussion |
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Consistent with our previous report,13 the present results show that disruption of the D2R gene results in increased blood pressure in both anesthetized and conscious mice. Previous results suggested that hypertension in D2–/– mice was unrelated to impairment of sodium excretion and was sensitive to blockade of
-adrenergic and endothelin B receptors.13 We now report that disruption of the D2R gene is associated with increased ROS production and oxidative stress, as reflected by the increased excretion of 8-isoprostane, a product of the nonenzymatic oxidation of arachidonic acid.16 Increased oxidative stress was associated with increased renal activity of NADPH oxidase, which is present not only in phagocytes, but also in many nonphagocytic cells, including endothelial, vascular smooth muscle, and mesangial cells, and proximal tubules in the kidney29–31 and is the major source of ROS in vascular and kidney tissues.16,32,33 NADPH oxidase is an enzymatic complex that consists of 5 subunits: membrane components p22phox and gp91phox (Nox2); cytosolic components p40phox, p47phox, and p67phox; and a low molecular weight G protein Rac1 or Rac2.16,31 Nox1 and Nox4, both Nox2 homologs, have been identified in the kidney. Nox1 is mainly expressed in vascular smooth muscle, whereas Nox4 has been shown to act as a superoxide anion producing NADPH oxidase in a number of tissues, including vascular smooth muscle and renal tubules,34 and to be the only constitutively active Nox, regulated at the level of gene expression rather than at the level of enzyme activity.29 Increased NADPH oxidase activity results from either an acute increase in the oxidase complex formation secondary to posttranslational modification of regulatory subunits or a chronic increase in the expression and abundance of component subunits.35 Indeed, we found increased renal mRNA and protein expression of Nox1, Nox2, and Nox4 in D2–/– mice, suggesting that D2R regulates NADPH oxidase activity by regulating Nox isoform expression.
The levels of ROS depend not only on their generation but also on their metabolism by antioxidant enzymes, such as HO, that degrades heme, a pro-oxidant, and generate biliverdin, an antioxidant.36,37 There are 2 HO isoforms, the inducible isoform HO-1 and HO-2, which is constitutively expressed in the kidney.36,37 Expressions of both HO-2 mRNA and protein were decreased in D2–/– mice, indicating that the regulation of ROS production by D2R involves both pro-oxidant and antioxidant systems.
The role of enhanced ROS production in the increased blood pressure of D2–/– mice was assessed by chronic administration of apocynin and acute administration of hemin. Both treatments normalized blood pressure in D2–/– mice, suggesting that activation of D2R may promote normal blood pressure by preventing excessive ROS production. Apocynin also decreased the excretion of 8-isoprostane in D2–/– mice to levels similar to those in D2+/+, an effect that was expected, because it decreases NADPH oxidase activity by preventing the assembly of the oxidase subunits rather than altering protein expression. However, apocynin increased the expressions of Nox2 and Nox4 isoforms only in D2–/– mice, an effect that may be compensatory to the decreased assembly of the oxidase complex.
One mechanism through which impaired D2R function may increase ROS is by affecting aldosterone production. D2Rs are present in the adrenal zona glomerulosa, and stimulation of D2R has a profound inhibitory effect on aldosterone production.38 The present study shows that aldosterone excretion is increased, and suppression of its secretion by high salt is impaired in the absence of normal D2R function. The role of aldosterone in increasing ROS production has been demonstrated extensively.17,39–41 Vascular oxidative stress associated with NADPH oxidase subunit overexpression and enhanced oxidase activity has been shown in mineralocorticoid hypertension and aldosterone-induced hypertension.39–41 In the kidney, the cortical mRNA expression of p22phox, Nox4, and Nox2 was increased in aldosterone-infused rats on a high-salt diet, and their expressions were normalized by treatment with a selective mineralocorticoid receptor antagonist.42 In rat mesangial cells, aldosterone stimulates the production of ROS through activation of NADPH oxidase.41
Spironolactone, an aldosterone antagonist, normalized blood pressure and the expression of Nox1 and Nox4 in D2–/– mice, indicating that the increased blood pressure and ROS production are mediated, in part, by impaired aldosterone regulation. However, although blood pressure was decreased, the excretion of 8-isoprostane was not, suggesting that increased ROS may not always result in increased blood pressure and that the effect of spironolactone on blood pressure may involve mechanisms other than decreased ROS production. The expression of Nox2 and HO-2 was not affected by the mineralocorticoid receptor antagonist, implying the existence of other mechanisms by which D2R regulates ROS production. In summary, our results show that D2Rs are involved in the regulation of ROS and aldosterone production and suggest that, by direct and indirect mechanisms, altered D2 expression or function may result in ROS-dependent hypertension.
Perspectives
Essential hypertension is a polygenic disease. The D2R gene is highly polymorphic, and several of its polymorphisms have not only been associated with high blood pressure and essential hypertension but have also been shown to result in decreased expression of the receptor. This study suggests that decreased D2R function may impair aldosterone secretion and increase ROS production and, thus, contribute to develop and/or maintain high blood pressure levels. Further studies are needed to clarify the mechanisms by which D2R directly regulates ROS production.
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Acknowledgments |
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Sources of Funding
This work was supported in part by grants from the National Institutes of Health (HL68686, HL23081, HL074940, DK52612, and DK39308).
Disclosures
None.
Received October 16, 2006; first decision November 1, 2006; accepted November 28, 2006.
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