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(Hypertension. 1997;30:859-867.)
© 1997 American Heart Association, Inc.
Articles |
Tissue Angiotensinogen Gene Expression Induced by Lipopolysaccharide in Hypertensive Rats
From the Second Department of Internal Medicine, Yokohama City (Japan) University School of Medicine.
Correspondence to Satoshi Umemura, MD, Second Department of Internal Medicine, Yokohama City University School of Medicine, 3-9, Fukuura, Kanazawa-ku, Yokohama 236, Japan.
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Abstract There is now convincing evidence that various tissues express their own tissue renin-angiotensin system, which may be regulated independently of the systemic renin-angiotensin system. However, little information is available on the regulation of the tissue renin-angiotensin system. We investigated the regulation of tissue angiotensinogen gene expression with respect to the development of hypertension. We measured basal and lipopolysaccharide-stimulated plasma angiotensinogen concentrations by radioimmunoassay and examined the expression of tissue angiotensinogen by Northern blot analysis in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) at 4 and 13 weeks of age. Basal plasma angiotensinogen concentration in SHR was comparable to that in WKY at 4 weeks of age and was significantly higher than that in WKY at 13 weeks of age. Lipopolysaccharide induced a significant increase in plasma angiotensinogen concentration in both WKY and SHR at 4 and 13 weeks of age. At 4 weeks of age, the basal levels of angiotensinogen mRNA in the liver, fat, adrenal, and aorta were higher in WKY than in SHR. At 13 weeks of age, the basal levels of angiotensinogen mRNA in the fat, adrenal, aorta, spleen, and kidney were higher in WKY than in SHR, while that in the liver did not differ significantly between the two strains. At 4 weeks of age, pretreatment with lipopolysaccharide increased the angiotensinogen mRNA levels in the liver, fat, adrenal, and aorta in both WKY and SHR. At 13 weeks of age, pretreatment with lipopolysaccharide increased the angiotensinogen mRNA levels in the liver, aorta, and adrenal; decreased those in the spleen; and had no effect in the kidney in both WKY and SHR. Interestingly, lipopolysaccharide increased the angiotensinogen mRNA level in fat only in SHR, with no effect in WKY, at 13 weeks of age. Lipopolysaccharide stimulated tumor necrosis factor-
mRNA expression in fat of WKY and
SHR, and the increase in tumor necrosis factor- mRNA level in SHR
was significantly greater than that in WKY. Therefore, the increased
tumor necrosis factor- mRNA expression may be involved in the
increased lipopolysaccharide-induced expression of
angiotensinogen gene in fat of SHR at 13 weeks of age.
These data suggest that the transcriptional and probably
posttranscriptional regulation of angiotensinogen mRNA
differs between SHR and WKY, that the regulation of
angiotensinogen gene expression is tissue-specific, and
that the altered expression of the angiotensinogen gene may
be involved in the development of hypertension.
Key Words: rats, inbred SHR • angiotensinogen • renin-angiotensin system • lipopolysaccharide • RNA, messenger • tumor necrosis factor-
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Introduction |
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Angiotensinogen is an important component of the systemic RAS, which participates in blood pressure regulation and electrolyte balance. The main source of the renin substrate angiotensinogen in plasma is the liver, where angiotensinogen is synthesized and secreted by the constitutive pathway into the bloodstream.1 A physiologically inactive decapeptide, Ang I, is released from angiotensinogen by renin and further hydrolyzed by ACE to produce the octapeptide Ang II, which mediates vasoconstriction and aldosterone secretion through specific interactions with Ang II receptors present on vascular smooth muscle and adrenal glands, respectively.2 Regulatory mechanisms for the synthesis and secretion of hepatic angiotensinogen have been extensively investigated in physiological and pathophysiological alterations. Inflammation,3 nephrectomy,4 and treatment with glucocorticoids,5 thyroid hormones,6 estrogens,7 or Ang II8 stimulate hepatic synthesis and secretion of angiotensinogen, increase circulating levels of angiotensinogen, and consequently elevate the activity of the circulating RAS.9 Recently, the existence of the tissue RAS has been established. Similar to the systemic RAS, the activity of most of this system is implicated in cardiovascular regulation. However, in contrast to the circulating system, the tissue RAS may be regulated by local factors, although definitive evidence supporting this claim is lacking. There is a strong correlation between blood pressure and plasma angiotensinogen.10 11 Several studies showed that PRA in SHR is either similar to or lower than that in normotensive rat strains.12 13 14 Moreover, plasma Ang II levels are not elevated in SHR.13 The tissue RAS may play an important role in hypertension and functions of the heart, adrenal gland, kidney, blood vessel wall, and adipose tissue. Recently, several experimental disease states have been shown to be associated with changes in angiotensinogen gene expression in affected organs. For example, an increase in angiotensinogen gene expression was seen in the heart after myocardial infarction15 or in the kidney exposed to arterial hypertension.16 Recent studies using cultured hepatocytes17 18 19 and transgenic animals20 21 22 reported that the 5' flanking region of the angiotensinogen gene might contain cis-acting regulatory elements. One crucial DNA control element, located between -531 and -557 in the rat gene 5' to the transcription start site, contains the sequence 5'-AGTTGGGATTTCCCAACC-3', which we have called the APRE.23 The APRE is a TNF-
–inducible enhancer that
confers TNF- induction onto an inert minimal promoter. The APR,
initiated experimentally by intraperitoneal LPS
injection and effected by the production of TNF-, is a
potent inducer of hepatic angiotensinogen expression. Past
studies have demonstrated an immune component in the pathogenesis of
systemic hypertension in both humans and animal models, including the
SHR.24 25 The SHR has been shown to exhibit thymocytotoxic
autoantibodies26 and impaired T- and B-cell
function.27 28 Thymic tissue obtained from normotensive
rats and implanted in the SHR reverses the T-cell dysfunction and
attenuates the subsequent development of hypertension.29
These results suggest a correlation between immunological abnormalities
and the development of hypertension in SHR. In the present study we
examined the regulation of angiotensinogen gene expression
by activation of the angiotensinogen gene APRE in various
tissues of SHR early in the developmental phase of hypertension (4
weeks of age) and when hypertension was established (13 weeks of age)
and compared findings with those in WKY. |
Methods |
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Animals
Male WKY and SHR were purchased from the Disease Model Cooperative Research Association (Kyoto, Japan) at 4 and 13 weeks of age. They were housed two to three animals per cage and maintained under controlled conditions of light, temperature, and humidity. All animals had free access to tap water and rat chow containing 0.3% NaCl. The rat chow was purchased from Oriental Kobo Kogyo.
Blood Pressure and Body Weight Measurements
SBP was measured by photoelectric volume oscillometry using an
automated tail-cuff sphygmomanometer (UR-5000, Ueda) at 4 and 13 weeks
of age.30 The reported values are averages of 10 to 15
consecutive measurements.
LPS Treatment
LPS (Escherichia coli, Sigma Chemical Co) in a dose
of 100 µg/kg was injected
intraperitoneally into 6 WKY or SHR at 4 weeks of
age and 15 WKY or SHR at 13 weeks of age. As controls, vehicle was
injected intraperitoneally into 6 WKY or SHR at 4
weeks of age and 15 WKY or SHR at 13 weeks of age. For measurement of
plasma RAS and analysis of angiotensinogen mRNA
expression, 6 hours after LPS stimulation all rats were decapitated.
For the analysis of TNF- mRNA, 1 hour after LPS stimulation
all rats were decapitated. The liver, aorta, adrenal, kidney, spleen,
and fat were removed and immediately frozen in liquid nitrogen. Fats
were isolated from epididymal fat pads.
Biochemical Assays
PRA was measured by radioimmunoassay.31 Briefly, 50
µL plasma was incubated for 1 hour at 37°C with 5 µL
8-hydroxyquinoline, 5 µL dimercaprol, 25 µL Na2EDTA
(4%), and 165 µL Tris acetate buffer (0.1 mol/L, pH 7.4)
containing 0.1% lysozyme, and the generated Ang I was measured with
the Renin Riabead Ang I kit (Dainabot Co, Ltd). For measurement of
plasma angiotensinogen (p-angiotensinogen)
concentration, 100 µL plasma was incubated for 5 hours at 37°C with
5 µL 8-hydroxyquinoline, 5 µL dimercaprol, 25 µL
Na2EDTA, 50 µL rat kidney renin, and 65 µL Tris acetate
buffer containing lysozyme, and the generated Ang I was measured by
radioimmunoassay. The p-angiotensinogen concentration was
expressed as picomoles Ang I equivalents per milliliter. Plasma Ang II
(p-Ang II) concentration was determined by a specific radioimmunoassay,
using an antibody to Ang II kindly provided by Dr Kazuaki Shimamoto
(Sapporo [Japan] Medical College).32
RNA Isolation and Analysis
Northern blot analysis was performed essentially as
described previously.33 34 Total RNA from tissues was
extracted with the guanidinium thiocyanate/cesium chloride
centrifugation method.35 RNA concentration
was determined by ultraviolet spectrophotometry. Each RNA sample (20
µg) was denatured with 1 mol/L glyoxal and 50% dimethyl
sulfoxide, electrophoresed on a 1.2% agarose gel, and transferred to
nylon membranes (GeneScreen Plus, DuPont–New England Nuclear). Filters
were prehybridized for 30 minutes at 60°C in a solution consisting of
1% sodium dodecyl sulfate, 1 mol/L NaCl, and 10%
dextran sulfate. Hybridization proceeded for 16 hours at 60°C in the
same solution containing 300 µg/mL denatured salmon sperm DNA
and 1x106 cpm/mL of the 32P-labeled rat
angiotensinogen cDNA probes36 or TNF- cDNA
probes.37 Filters were washed twice with 2x SSC (1x
SSC=0.15 mol/L NaCl, 0.015 mol/L sodium citrate) for 5
minutes at room temperature, twice with 2x SSC and 1% sodium
dodecyl sulfate for 30 minutes at 60°C, and twice with 0.1x
SSC for 15 minutes at room temperature. Dried filters underwent
autoradiography at -70°C with an intensifying
screen. Expression of angiotensinogen mRNA or TNF- mRNA
was measured with a Fujix Bio-Imaging Analyzer (BAS 2000, Fuji
Photo Film) and normalized to the signal generated by probing for the
constitutively expressed GAPDH gene.38 A 1089-bp
Aat I–Aat II cDNA fragment of the rat
angiotensinogen gene, which was kindly provided by Drs
Shigetada Nakanishi (Kyoto University) and Hiroaki Ohkubo (Kumamoto
University), was used as a hybridization probe.36 The
TNF- cDNA probe was kindly provided Asahi Chemical Industry. The
GAPDH cDNA probe used was a generous gift of Dr Ray Wu (Cornell
University, Ithaca, NY).38
Statistical Analysis
For the statistical analysis of differences among
groups, the unpaired Student's t test was used. All
quantifiable data are expressed as mean±SE.
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Results |
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Characteristics and LPS-Induced Change in Plasma RAS in WKY and SHR
SBP, body weight, and wet tissue weights of kidney and heart in WKY and SHR are summarized in the Table
.
The SBP of SHR at 4 weeks of age was statistically higher than that of
age-matched WKY (P<.0001) and increased further at 13 weeks
of age compared with that of WKY (P<.0001). Concomitant
with the blood pressure increase, the ratio of wet tissue weight of
heart to body weight in SHR became significantly greater at 13 weeks of
age. No such difference was observed between WKY and SHR with respect
to the ratio of wet tissue weight of kidney to body weight at 4 and 13
weeks of age. As shown in Fig 1, basal
PRA and p-Ang II in SHR were comparable to values in age-matched WKY.
In SHR, LPS induced a significant increase in p-Ang II at 13 weeks of
age, but in WKY the change was not significant. On the other hand, LPS
induced no significant change in PRA in either WKY or SHR at both 4 and
13 weeks of age. Basal p-angiotensinogen concentration in
SHR was significantly higher than in WKY at 13 weeks of age, and LPS
induced a significant increase in p-angiotensinogen
concentration in both WKY and SHR at both 4 and 13 weeks of age. SBP in
basal conditions was significantly correlated with
p-angiotensinogen concentration (r=.611,
P<.001).
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Tissue-Specific and LPS-Induced Expression of
Angiotensinogen mRNA in WKY and SHR
The angiotensinogen gene is expressed mainly in the
liver, but it is also expressed in the fat, adrenal, aorta, kidney, and
spleen. As shown in Fig 2, basal liver
angiotensinogen mRNA levels in WKY were significantly
higher than those in SHR at 4 weeks of age and comparable to those in
SHR at 13 weeks of age. As shown in Figs 3, 4, and 5,
the expression of basal angiotensinogen mRNA in fat,
adrenal, and aorta was suppressed in SHR compared with WKY at 4 and 13
weeks of age. As shown in Fig 6, basal
angiotensinogen mRNA levels in spleen and kidney were lower
in SHR than in WKY at 13 weeks of age. A previous study reported that
liver angiotensinogen mRNA levels rapidly increased during
the first 5 hours and reached a maximal level at 5 to 10 hours after
LPS administration.39 Therefore, we examined the
expression of angiotensinogen mRNA 6 hours after LPS
administration. Treatment with LPS for 6 hours increased
angiotensinogen mRNA levels in liver, adrenal, and aorta in
both WKY and SHR at 4 and 13 weeks of age (Figs 2, 4, and 5). LPS
decreased angiotensinogen mRNA levels in spleen, and had no
effect on levels in the kidney in both WKY and SHR at 13 weeks of age
(Fig 6). Although we also examined basal and LPS-induced
angiotensinogen mRNA expression in the spleen and kidney at
4 weeks of age, we could not detect angiotensinogen mRNA
expression in the basal and LPS-induced state (data not shown). LPS
increased angiotensinogen mRNA level in fat in both WKY and
SHR at 4 weeks of age. However, at 13 weeks of age, LPS increased the
angiotensinogen mRNA level only in SHR, with no effect in
WKY (Fig 3).
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LPS-Induced Expression of TNF- mRNA in WKY and SHR
In most tissues, the response of angiotensinogen gene
expression to LPS was comparable in WKY and SHR. The only exception was
fat tissue at 13 weeks of age. Recent studies showed that TNF- is
expressed in adipose tissue,40 and another study suggested
that TNF- was involved in the induction of
angiotensinogen gene expression by
inflammation.41 Thus, we examined LPS-induced TNF- mRNA
expression in fat and liver of WKY and SHR at 13 weeks of age. First,
we examined the expression of TNF- mRNA 6 hours after LPS
administration. However, we could not detect TNF- mRNA in basal and
LPS-stimulated levels in fat and liver of WKY and SHR at 13 weeks of
age (data not shown). Previous study reported that the maximal
induction of TNF- mRNA is 1 hour after LPS
administration37 ; therefore, we examined the expression of
TNF- mRNA 1 hour after LPS administration. As shown in Fig 7, we could not detect basal TNF- mRNA
in both WKY and SHR in liver and fat. LPS stimulated TNF- mRNA
expression in the fat of WKY and SHR, and the induction of TNF- mRNA
level in SHR was significantly greater than that in WKY.
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Discussion |
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In the present study, basal p-angiotensinogen levels did not differ between SHR and WKY at 4 weeks of age, although SHR had a higher SBP than WKY. At 13 weeks of age, SBP in SHR elevated farther, and basal p-angiotensinogen levels increased significantly in SHR to a level higher than that in WKY (Fig 1
).
Furthermore, SBP was significantly correlated with
p-angiotensinogen concentration (r=.611,
P<.001) in WKY as well as in SHR. On the other hand, SBP
showed no relationship with PRA and p-Ang II. These results confirm our
previous study using WKY and SHR at 6 and 14 weeks of
age,42 and we speculate that the increase in
p-angiotensinogen levels in SHR at 13 weeks of age promotes
further development of hypertension as well as secondary changes in
response to hypertension rather than being the primary pathogenic
mechanism of hypertension. Although at 13 weeks of age basal
p-angiotensinogen concentration in SHR was significantly
higher than that in WKY, basal p-Ang II concentration was comparable in
both strains. In addition, basal PRA in SHR was comparable to that in
WKY. A previous study showed that plasma ACE activity in WKY at 4 and
18 weeks of age was higher than that in age-matched SHR.43
The results of the present study suggested that the basal plasma
ACE activity in WKY is higher than that in SHR. Therefore, basal p-Ang
II in SHR may be comparable to that in WKY. Previous studies reported that treatment with 100 µg/kg LPS in Wistar rats significantly increased p-angiotensinogen during the first 12 hours.39 44 In the present study, injection of LPS produced a significant increase in p-angiotensinogen concentration in both WKY and SHR at 4 and 13 weeks of age. On the other hand, LPS induced a significant increase in Ang II in SHR but no significant change in WKY at 13 weeks of age. The main factors limiting the rate of Ang II production are angiotensinogen, PRA, and ACE. LPS induced no significant changes in PRA in either WKY or SHR. It was reported that the regulation of ACE in vascular tissues differs between SHR and WKY and that the level of ACE activity in plasma and vascular tissue may be regulated in a different manner within a given rat strain.43 Therefore, the finding that pretreatment with LPS did not alter p-Ang II level in WKY despite an increase in p-angiotensinogen level may be due to differences in the regulation of plasma ACE activity between SHR and WKY at 13 weeks of age.
In the present study, although the expression of basal angiotensinogen mRNA levels in all tissues including the liver was suppressed in SHR compared with WKY at 4 weeks of age, basal p-angiotensinogen levels were not different between SHR and WKY at 4 weeks of age. Furthermore, although the expression of basal angiotensinogen mRNA levels in most tissues was suppressed in SHR compared with WKY, there was no significant difference in the liver at 13 weeks of age. In contrast, basal p-angiotensinogen level was higher in SHR than WKY at 13 weeks of age. These discrepancies between angiotensinogen mRNA levels and p-angiotensinogen are consistent with previous studies.42 45 All available evidence indicates that p-angiotensinogen is secreted only constitutively and cannot be stored within secretory granules.46 This implies that angiotensinogen production is controlled mostly at the transcriptional and posttranscriptional levels of the angiotensinogen gene. Consequently, the discrepancy between the basal mRNA level and basal plasma concentration may be due to differences between SHR and WKY in transcriptional or posttranscriptional regulation of angiotensinogen mRNA. For example, glucocorticoids, despite their strong effect on transcription of the angiotensinogen gene, may have opposing effects on translation of its mRNA.47 In contrast to glucocorticoids, estrogens and thyroid hormones affect both angiotensinogen secretion and liver angiotensinogen mRNA expression to a comparable extent. In addition, Ang II increases the synthesis of angiotensinogen in hepatocytes by stabilizing angiotensinogen mRNA.5 In previous study, Lodwick et al45 reported no difference in the level of circulating angiotensinogen between 25-week-old SHR and WKY on either a normal or high salt diet, whereas they found a higher level of angiotensinogen mRNA in WKY liver compared with SHR liver. Since plasma renin concentration was different between the strains, they suggested that a relatively higher consumption of angiotensinogen in WKY may at least partly account for the similar p-angiotensinogen. Therefore, the discrepancy between p-angiotensinogen concentration and liver angiotensinogen mRNA levels at 4 and 13 weeks of age in the present study may be due to altered translational machinery of angiotensinogen mRNA in the liver and a difference in the metabolism rate of angiotensinogen in the circulation and/or peripheral tissues. However, the exact mechanism should be examined by future study.
The 5' flanking region of the angiotensinogen gene contains
cis-acting regulatory elements. Analysis of this
region of rat and human genes has shown consensus sequences for a
glucocorticoid response element, a thyroid response element, an
estrogen response element, and APRE. Most previous studies testing the
effect of glucocorticoids in vivo have used doses about 100 times
higher than that required to induce hypercorticism. Administration of
corticosterone at doses that induced clear signs of hypercorticism did
not stimulate p-angiotensinogen.48 These data
make it unlikely that glucocorticoids act as primary regulators of
angiotensinogen. Rather, glucocorticoids may function as
permissive factors that facilitate the actions of other agents, such as
interleukins. In contrast, the APR, initiated experimentally by
intraperitoneal administration of bacterial LPS, is
a potent inducer of hepatic angiotensinogen
expression.23 39 In previous studies, initiation of
systemic inflammation by a single dose of
intraperitoneal LPS resulted in a fivefold increase
in hepatic steady-state mRNA levels at 3 hours23 and a
threefold increase in p-angiotensinogen concentration at 8
hours.49 In the LPS-induced APR, the
macrophage-derived cytokines TNF- and
interleukin-6 are likely to be the activators of hepatic
angiotensinogen gene expression.41 50 51 LPS
in the bloodstream rapidly binds to the serum protein, referred to as
lipopolysaccharide binding protein (LBP).52
Complexes of LPS and LBP bind macrophage surface protein
CD14.53 Circulating cytokines are secreted from
activated macrophages. The cytokines
interleukin-6 and TNF- bind to specific receptors, activating second
messenger signaling cascades that ultimately control the nuclear
expression of the two transcription factor families that bind to the
APRE. The p65 subunit of nuclear factor-
B (Rel A)/nuclear
factor-B1 (NF-B1) is a transcription factor complex associated
with inhibitory protein (IB). Rel A/NF-B1 is released
from inhibitors in response to cytokine signaling
events, allowing it to translocate into the nucleus and stimulate
transcription of the angiotensinogen
gene.41 50 54 55 56
Pretreatment with LPS increased angiotensinogen mRNA levels in the liver, aorta, and adrenal in both WKY and SHR at 4 and 13 weeks of age, decreased levels in the spleen, and had no effect on levels in the kidney in both WKY and SHR at 13 weeks of age. This indicates that LPS-mediated regulation of angiotensinogen gene expression is tissue-specific. After pretreatment with LPS, angiotensinogen mRNA levels in most tissues in SHR, with the exception of fat, were similar to those in WKY at 4 and 13 weeks of age. In fat, LPS increased angiotensinogen mRNA in both WKY and SHR at 4 weeks of age, whereas LPS increased angiotensinogen mRNA in SHR but not in WKY at 13 weeks of age. Angiotensinogen is expressed abundantly in adipose tissue, and angiotensinogen gene expression increases during adipogenic differentiation.57 A previous study showed that angiotensinogen gene expression in adipocytes was nutritionally regulated and that blood pressure was modulated by fasting and refeeding in a manner that paralleled the adipocyte angiotensinogen mRNA level, irrespective of no change in either the hepatic angiotensinogen mRNA level or p-angiotensinogen concentration.58
Several inflammatory mediators, including TNF-, interleukin-6, and
interleukin-1, were induced by LPS stimulation. This complexity of
factors participates in the regulation of angiotensinogen.
Previous studies reported that TNF- and interleukin-6
activate angiotensinogen gene
expression.41 50 51 In contrast, interleukin-1 decreased
the angiotensinogen secretion and
angiotensinogen gene expression in
hepatocytes.51 In particular, local
production of TNF- may have important roles in regulating
lipolysis, insulin sensitivity, and angiotensinogen
expression in the tissue RAS in fat deposits.41 59 60 61 In
the present study, although LPS induced TNF- mRNA in both WKY
and SHR, the induction of TNF- mRNA level in SHR was significantly
greater than that in WKY. These results suggest that the enhanced
expression of TNF- gene in fat may be involved in the LPS-mediated
activation of the fat angiotensinogen gene in SHR at 13
weeks of age. Many studies suggest that immunological mechanisms may
contribute to the development of hypertension in
humans24 25 and animals.28 The differences
that we observed between SHR and WKY may involve immunological
abnormalities in SHR, and regulation of angiotensinogen
gene expression in fat may play a part in the development of
hypertension.
In conclusion, our data indicate that the LPS-mediated regulation of angiotensinogen gene expression is tissue-specific. Our results also suggest that altered angiotensinogen gene expression in fat is involved in the development of hypertension in SHR.
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Acknowledgments |
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This study was supported in part by grants from the Ministry of Education, Science, Sports, and Culture of Japan; the Uehara Memorial Foundation; and the Yokohama Foundation for Advancement of Medical Science.
Received October 7, 1996; first decision November 6, 1996; accepted March 17, 1997.
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