(Hypertension. 1996;27:1216-1223.)
© 1996 American Heart Association, Inc.
Articles |
Tissue-Specific Regulation of Angiotensinogen Gene Expression in Spontaneously Hypertensive Rats
From the Second (K. Tamura, S.U., N.N., S.Y., T.I., N.T., M.I.) and Third (T.Y., S.T., H.S.) Departments of Internal Medicine, Yokohama City (Japan) University School of Medicine, and Institute of Applied Biochemistry, University of Tsukuba, Ibaraki, Japan (K. Tanimoto, K.M.).
Correspondence to Kouichi Tamura, MD, Second Department of Internal Medicine, Yokohama City University School of Medicine, 3-9, Fukuura, Kanazawa-Ku, Yokohama 236, Japan.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract Angiotensinogen is expressed in many tissues besides the liver. Recent studies have suggested that abnormalities in the regulation of angiotensinogen gene expression may be involved in the development of hypertension. However, little information is available concerning the functional significance of tissue angiotensinogen. In this study, we measured plasma angiotensinogen concentration by radioimmunoassay and examined the expression of tissue angiotensinogen by Northern blot analysis in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Although plasma angiotensinogen concentration in SHR was comparable to that in WKY at 6 weeks of age, it was increased significantly at 14 weeks of age in SHR and became higher than that in WKY. The levels of hepatic angiotensinogen mRNA were similar in SHR and WKY, and the levels of aortic, adrenal, and renal angiotensinogen mRNAs were lower in SHR than in WKY at both 6 and 14 weeks of age. Brain angiotensinogen expression in SHR was higher than in WKY at 6 weeks of age and was comparable to that in WKY at 14 weeks of age. On the other hand, cardiac and fat angiotensinogen mRNA levels were significantly increased at 14 weeks of age in SHR. These results demonstrate that the expression of tissue angiotensinogen is regulated differently in SHR and WKY and indicate that the development of hypertension is accompanied at least temporally with increases in plasma angiotensinogen concentration as well as cardiac and adipogenic angiotensinogen mRNA in SHR.
Key Words: rats, inbred SHR • gene expression • angiotensinogen • renin-angiotensin system • RNA, messenger
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Recent advances in molecular biology have demonstrated that hypertension develops as a complex pathological state with a specific genetic background involving various hormonal and neuronal systems. Among these, the RAS exerts a major influence on the determination of blood pressure as well as sodium and extracellular fluid balance through generation of Ang II, which has a variety of actions such as vasoconstrictor activity and stimulation of the production and release of aldosterone. The profound participation of the RAS in several cardiovascular diseases including hypertension has now been proposed, and accumulating evidence from biochemical and molecular studies of angiotensin physiology have raised the possibility that local RASs with different regulatory mechanisms may exist as distinct systems from the classic plasma RAS.1 2 3 Local RASs may exist and function in the brain, heart, adrenal gland, kidney, blood vessel wall, and adipose tissue. Whether all the components of the RAS are physiologically relevant is controversial, and the exact role of the local RAS remains elusive, but it is interesting to speculate that a local RAS may increase the effects of Ang II on a particular tissue in specific physiological and pathophysiological processes.
Angiotensinogen is the unique substrate of renin in vivo in the RAS, and it is generally accepted that the primary source of plasma angiotensinogen (p-angiotensinogen) is the liver. One important question is whether angiotensinogen regulates RAS activity or is solely an extracellular reservoir of angiotensin peptides. Several studies have suggested that angiotensinogen has an active regulatory function in both circulating blood and local tissues under both physiological and pathophysiological conditions.1 In epidemiological studies, p-angiotensinogen and blood pressure were found to be positively correlated.4 5 6 In addition, recent genetic linkage analyses of the human angiotensinogen gene with high blood pressure7 8 and transgenic studies using the rat and human angiotensinogen genes9 10 11 have suggested that the transcriptional mechanism of the angiotensinogen gene is involved in the pathogenesis of hypertension. Furthermore, angiotensinogen-deficient mice have been developed by homologous recombination in mouse embryonic stem cells. These mice do not produce angiotensinogen and are hypotensive, indicating the critical importance of angiotensinogen in the maintenance of blood pressure and development of hypertension.12 13
The SHR is an inbred strain that develops high blood pressure with increasing age and is widely used as a model of human hypertension. Similarly to most patients with essential hypertension, SHR have normal or decreased PRA and plasma Ang II (p–Ang II) concentration relative to their normotensive counterpart, the WKY. Nevertheless, previous results demonstrated a participation of the RAS in the maintenance of hypertension in SHR.14 15 In recent studies, antisense oligonucleotides that inhibit angiotensinogen gene expression decreased blood pressure significantly in SHR, thereby suggesting that angiotensinogen plays a role in the pathogenesis of hypertension and/or structural or functional changes known to occur in response to hypertension.16 17 In this study, we systematically examined the tissue-specific regulation of angiotensinogen gene expression in SHR early in the developmental phase of the hypertension (6 weeks of age) and when hypertension was established (14 weeks of age) and compared the findings with those in WKY. We also examined the relationship between the regulation of tissue angiotensinogen gene expression and the plasma RAS in SHR.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Animals
Male SHR and WKY were purchased from Charles River Japan Inc (Atsugi, Kanagawa, Japan) at 4 weeks of age. The rats were housed two to three per cage and maintained under controlled conditions of light, temperature, and humidity. All rats had free access to tap water and rat chow with 0.3% NaCl (Oriental Kobo Kogyo).
Blood Pressure Measurement
SBP was measured by the photoelectric volume oscillometric
method with a UR-5000 automated tail-cuff sphygmomanometer
(Ueda).18 Values are shown as averages of 10 to 15
consecutive determinations. At the age of 6 weeks, 16 rats from SHR or
WKY were chosen randomly and killed instantly by decapitation.
The remaining 16 rats were kept on the same diets for up to 14 weeks of
age and then killed in the same way. Brain, aortas, heart, liver,
spleen, adrenals, kidneys, and epididymal fat were dissected out and
immediately frozen in liquid nitrogen.
Biochemical Assays
PRA was measured by radioimmunoassay.19 Briefly, 50
µL plasma was incubated 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
for 1 hour at 37°C; the generated Ang I was measured with a Renin
Riabead Angiotensin I kit (Dainabot Co, Ltd). For
measurement of p-angiotensinogen concentration, 100
µL plasma was incubated with 5 µL 8-hydroxyquinoline, 5 µL
dimercaprol, 25 µL Na2EDTA, 50 µL rat kidney renin, and
65 µL Tris-acetate buffer containing lysozyme for 5 hours at
37°C; the generated Ang I was measured by
radioimmunoassay.19 p–Ang II was determined by a specific
direct radioimmunoassay with an anti–Ang II antibody as described
previously, without extraction procedure.20
RNA Isolation and Analysis
Northern blot analysis was performed essentially as
described previously.21 22 Total RNA from tissues was
extracted with the guanidinium thiocyanate/cesium chloride
centrifugation method.23 Each RNA sample
(20 µg) was denatured with 1 mol/L glyoxal and 50% dimethyl
sulfoxide, electrophoresed on 1.2% agarose gels, and transferred onto
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 mg/mL denatured salmon sperm DNA and
1x106 cpm/mL of the 32P-labeled rat
angiotensinogen cDNA probes.24 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 were
subjected to autoradiography at -70°C with
an intensifying screen. Expression of angiotensinogen mRNA
was quantified with a FUJIX BIO-Imaging Analyzer BAS2000 (Fuji
Photo Film) and normalized to the signal generated by probing for the
constitutively expressed GAPDH gene.25
Statistical Analysis
For statistical analysis of differences among groups,
unpaired Student's t test or ANOVA followed by
Scheffé's F test were used. Univariate correlation
analysis was used for examination of relations between
parameters. All quantitative data are expressed as
mean±SE.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Characteristics and Plasma RAS of WKY and SHR
SBP, body weight, and wet tissue weights of kidney and heart in SHR and WKY are summarized in the Table
. The SBP of SHR
at 6 weeks of age was statistically higher than that of age-matched
WKY (P<.01) and increased further at 14 weeks of age
compared with that of WKY (P<.01). Concomitant with the
blood pressure increase, the ratio of wet tissue weight of heart to
body weight in SHR became significantly greater at 14 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 14 weeks of age,
although this ratio in SHR was greater at 6 weeks of age.
|
As shown in Fig 1, PRA and p–Ang II in SHR were lower
than or comparable to values in WKY. On the other hand,
p-angiotensinogen in SHR was significantly higher than
in WKY at 14 weeks of age, and SBP was significantly correlated with
p-angiotensinogen (r=.857,
P<.0001).
|
Tissue-Specific Regulation of Angiotensinogen mRNA
Expression in WKY and SHR
Angiotensinogen is expressed mainly in the liver but
is also expressed abundantly in the brain, aortas, adrenals, kidneys,
and fat.1 2 In addition, angiotensinogen mRNA
has been detected in small quantities in the heart and
spleen.1 2 We first analyzed the steady-state
mRNA levels for hepatic angiotensinogen in SHR and WKY at 6
and 14 weeks of age. As shown in Fig 2, the levels of
hepatic angiotensinogen mRNA were similar between SHR and
WKY at 6 and 14 weeks of age. Since this result could not explain the
increase in p-angiotensinogen in SHR at 14 weeks of
age, we measured angiotensinogen mRNA levels in other
tissues. Brain angiotensinogen mRNA levels in SHR were
significantly higher than those in WKY at 6 weeks of age and comparable
to those in WKY at 14 weeks of age. The expression of
angiotensinogen mRNA in the aortas, adrenals, and kidneys
was suppressed in SHR compared with WKY at 6 and 14 weeks of age (Figs 3 and 4). Although steady-state
angiotensinogen mRNA levels in fat were lower in SHR than
WKY at 6 weeks of age, the mRNA levels in SHR increased significantly
toward values similar to those in WKY at 14 weeks of age (Fig 4).
Angiotensinogen mRNA levels in the spleen and heart were
very low at 6 weeks of age, and no difference was observed between SHR
and WKY at this age (Fig 5). At 14 weeks of age,
although increases in cardiac angiotensinogen mRNA levels
were observed in both SHR and WKY, the relative mRNA levels in SHR were
significantly higher than those in WKY. In addition, the
steady-state cardiac angiotensinogen mRNA levels were
significantly correlated with SBP (r=.857,
P<.0001) and p-angiotensinogen
(r=.840, P<.0001). The relationship between
cardiac and fat angiotensinogen mRNA levels was weak but
statistically significant (r=.448, P<.05). In
contrast to cardiac angiotensinogen expression, an increase
in angiotensinogen mRNA expression was observed in the
spleen of WKY at 14 weeks of age (Fig 5).
|
|
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Previous studies of the regulation of the RAS components in SHR showed widespread abnormalities of renin gene expression in SHR that were modulated in some tissues by the development of hypertension26 and demonstrated an increase in the activity of vascular ACE in SHR.27 In the present study, we showed that p-angiotensinogen levels were increased significantly with the development of hypertension and demonstrated that angiotensinogen gene expression was regulated in a tissue-specific manner by the development of hypertension in SHR.
In our experiment, p-angiotensinogen levels did not
differ between SHR and WKY at 6 weeks of age although SHR had a higher
SBP than WKY. At 14 weeks of age, SBP in SHR further elevated, and
p-angiotensinogen increased significantly in SHR to a level
higher than that in WKY (Fig 1
). This result indicates that
p-angiotensinogen in SHR is similar to that in WKY
early in the developmental phase of hypertension in SHR and
significantly higher than that in WKY when hypertension is established.
Indeed, SBP was significantly correlated with
p-angiotensinogen (r=.857,
P<.0001) in WKY as well as in SHR. On the other hand, SBP
showed no relationship with PRA and an inverse relationship with p–Ang
II (r=-.609, P<.0001). Therefore,
p-angiotensinogen level was increased significantly,
and PRA and p–Ang II were not elevated by hypertension in SHR.
Our results are consistent with those of previous studies which
showed that p-angiotensinogen levels in patients with
essential hypertension were higher than in normotensive subjects
irrespective of the lack of significant increases in other components
of the RAS (PRA, ACE, Ang II, aldosterone).4 5
Although SHR had higher SBP than WKY at 6 weeks of age,
p-angiotensinogen levels did not differ significantly
between SHR and WKY at this age. Therefore, we speculate that the
increase in p-angiotensinogen in SHR at 14 weeks of age
is the promoter of further development of hypertension as well as
secondary changes in response to hypertension rather than the
primary pathogenic mechanism of hypertension.
It is generally accepted that p-angiotensinogen level is determined primarily by angiotensinogen derived from the liver. The functional influences on p-angiotensinogen of angiotensinogen synthesized in a variety of tissues other than the liver are not fully understood. In our results, although p-angiotensinogen levels in SHR were significantly higher than in WKY at 14 weeks of age, hepatic angiotensinogen mRNA levels were not different between SHR and WKY at 14 weeks of age. This was consistent with results of previous studies in which the hepatic expression of the angiotensinogen gene in SHR was not elevated compared with that in WKY.28 29 Accumulated evidence has indicated that angiotensinogen is secreted only constitutively and cannot be stored within secretory granules, suggesting that angiotensinogen production is controlled mostly at the level of synthesis rather than of secretion.30 31 32 For example, steroid hormones such as dexamethasone and estradiol induced an increase in angiotensinogen mRNA and secretion, with the same characteristics as in hepatocytes.33 In addition, Ang II enhanced hepatic angiotensinogen synthesis by a stabilizing effect of Ang II on angiotensinogen mRNA rather than by an increase in transcription rate.34 In a previous study, dihydrotestosterone induced an increase in angiotensinogen mRNA, which was not accompanied by an increased angiotensinogen secretion.33 Although no convincing explanation was given for this discrepancy between the mRNA level and angiotensinogen secretion, the authors suggested that transient sequestration of mRNA into a nondegradable and, at the same time, nontranslatable form or compartment might have a role in the discrepancy, as observed in cells exposed to stress or in developmental systems.33 35 36 Thus, it is possible that a similar situation might be responsible for the difference between the p-angiotensinogen concentration and hepatic angiotensinogen mRNA level. Recently, Lodwick et al37 reported no difference in circulating angiotensinogen level 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. Plasma renin concentrations also differed between the strains in their study, and they suggested that a relatively higher consumption of angiotensinogen in WKY might at least partly account for the similar p-angiotensinogen levels.37 Therefore, altered translational machinery from angiotensinogen mRNA in the liver and difference in the metabolism rate of angiotensinogen in the circulation and/or peripheral tissues might be responsible for the discrepancy between the p-angiotensinogen concentrations and hepatic angiotensinogen mRNA levels in SHR and WKY, although the exact mechanism should be determined by future study.
In the brain, angiotensinogen mRNA levels were higher in SHR than WKY at 6 weeks of age. The enhanced brain angiotensinogen gene expression in the early stage of hypertension in SHR in the present study is consistent with previous results,29 38 39 and recent studies using antisense oligonucleotides corresponding to angiotensinogen mRNA indicated an important role of brain angiotensinogen in the pathogenesis of hypertension in SHR.16 At 14 weeks of age, brain angiotensinogen mRNA levels were similar in SHR and WKY. Previous studies showed that low but measurable levels of angiotensinogen mRNA were spread diffusely throughout the brain, and intense angiotensinogen gene expression was found in the brain stem and mid-brain.29 38 Elevated expression of brain angiotensinogen mRNA in SHR was reported to be localized mainly in these areas.29 38 Since we measured angiotensinogen mRNA levels using total RNA extracted from whole brain, we could not detect elevated brain angiotensinogen expression in SHR at 14 weeks of age. Our results suggest that brain angiotensinogen expression is increased significantly early in the developmental phase of hypertension in SHR, with a concomitant increase in brain Ang II content.39 However, the influence of this increase in brain angiotensinogen on p-angiotensinogen seems to be small because of the blood-brain barrier.
In the aortas, adrenals, and kidneys, angiotensinogen mRNA levels in SHR were lower than in WKY at both 6 and 14 weeks of age. Angiotensinogen mRNA is expressed in the medial smooth muscle and periadventitial fat of the aortic wall, and the levels of medial angiotensinogen mRNA were found to be locally regulated by sodium intake and sympathetic activation.40 Previous studies showed an increase in aortic ACE activity in SHR27 and elevations of aortic angiotensinogen and ACE mRNA levels in experimental models of hypertension.41 In our study, however, the level of expression of aortic angiotensinogen mRNA in SHR was lower than in WKY during the development of hypertension. This result is consistent with previous observations in which angiotensinogen locally produced in the vascular wall of arterioles did not have a major role in the regulation of vascular angiotensin release in experimental models42 or in the enhanced arteriolar constriction in the microcirculation of SHR.15 Furthermore, our results suggest that pressure overload is not a positive regulator of aortic angiotensinogen mRNA expression in SHR.
Several reports have implicated the kidney in the pathogenesis of hypertension in SHR.43 44 Renal transplantation studies showed that blood pressure of the donor SHR was transplanted with the kidney.43 Genetic studies revealed a cosegregation of renal hemodynamics and blood pressure in SHR45 and found that a reduced afferent arteriolar diameter at 7 weeks of age was a predictor of increased blood pressure at 23 weeks in an F2 generation from SHR and WKY.46 In the present study, the ratio of wet tissue weight of kidney to body weight in SHR was greater than that in WKY at 6 weeks of age, supporting a possible role of the kidney in the development of hypertension in SHR. It has also been hypothesized that the components of the renal RAS act together to regulate sodium and water balance intrarenally, and locally produced Ang II in the kidney may also be involved in adaptive processes during hypertension and heart failure.47 48 In previous studies, Ang II levels in the kidney were found to correlate well with both angiotensinogen gene expression and angiotensinogen concentration in the kidney,49 and the renal angiotensinogen mRNA level was specifically increased in an experimental heart failure model.50 In addition, altered regulation of renal angiotensinogen expression by sodium balance was reported in SHR.28 With respect to the adrenals, previous studies showed that renin activity and Ang II concentration were increased in the adrenal gland in hypertensive rats.51 52 53 However, in the present study, steady-state mRNA levels for adrenal and renal angiotensinogen were lower in SHR than in WKY early in the developmental phase of the hypertension and after the establishment of hypertension in SHR. Our results indicate that the expression of adrenal and renal angiotensinogen is not activated in SHR at least in the basal state.
Angiotensinogen is expressed abundantly in adipose tissue, and angiotensinogen gene expression increases during adipogenic differentiation.21 Although the physiological and pathological significance of the adipogenic angiotensinogen is not fully understood, a previous study showed that angiotensinogen gene expression in adipocytes was nutritionally regulated and blood pressure was modulated by fasting and refeeding in a manner that paralleled adipocyte angiotensinogen mRNA level irrespective of the lack of apparent changes in the hepatic angiotensinogen mRNA level.54 In the present study, although the steady-state levels of fat angiotensinogen mRNA in SHR were lower than those in WKY at 6 weeks of age, the mRNA level in SHR increased significantly with the development of hypertension at 14 weeks of age and reached a level comparable to that in WKY. This result suggests that angiotensinogen derived from fat may have a role in the development of hypertension in SHR.
The steady-state mRNA levels for angiotensinogen in the spleen and heart were extremely low and did not show any differences between SHR and WKY early in the development of hypertension. At 14 weeks of age, the splenic angiotensinogen mRNA level in WKY was increased slightly but statistically significantly. In contrast to splenic angiotensinogen mRNA, cardiac angiotensinogen mRNA showed a marked increase concomitant with cardiac hypertrophy at 14 weeks of age when hypertension was established in SHR. The heart is one of the most sensitive target organs with regard to the actions of Ang II. A possible role for the RAS in mediating pathological cardiac growth derives from the observation that ACE inhibitors and Ang II type I receptor antagonists can prevent or reverse hypertensive cardiac hypertrophy.55 Local production of angiotensinogen, renin, ACE, and mRNA as well as the presence of Ang II receptors were confirmed in rat and human myocardium, suggesting strongly the existence of a local RAS in the heart,1 2 3 although the cardiac renin activity was shown to be mainly derived from uptake of circulating renal renin.56
With respect to the regulation of cardiac angiotensinogen expression, stretch stimuli increased angiotensinogen mRNA expression in cardiomyocytes in vitro.57 In addition, although angiotensinogen mRNA levels were extremely low in the heart, significant increases were observed in the left ventricle in models of pressure-overload cardiac hypertrophy.58 Furthermore, balloon injury activated angiotensinogen gene expression in the medial layer of the aortas,59 and a molecular variant of angiotensinogen was found to be related to coronary atherosclerosis, as evaluated by coronary angiography.60 These previous and our present results indicate an important role of cardiac angiotensinogen in the pathophysiology of several cardiovascular diseases.
In conclusion, the regulation of tissue angiotensinogen differed between SHR and WKY. p-Angiotensinogen and steady-state mRNA levels for cardiac and fat angiotensinogen increased in SHR during the development of hypertension, irrespective of the lack of changes in hepatic angiotensinogen expression. Cardiac angiotensinogen mRNA levels were significantly correlated with SBP and p-angiotensinogen. These results suggest that the development of hypertension is, at least temporally, followed by increases in angiotensinogen expression in a tissue-specific manner. The elevation of p-angiotensinogen and activation of tissue angiotensinogen may increase Ang II production at local tissue sites irrespective of the lack of increases in PRA and p–Ang II, resulting in the further development of hypertension and cardiac hypertrophy in SHR.
|
Selected Abbreviations and Acronyms |
|---|
|
|
Acknowledgments |
|---|
This work was supported in part by grants from the Ministry of Education, Science, and Culture of Japan (Nos. 06274224, 07266221, 05670956, and 4512); the Uehara Memorial Foundation; and Kanagawa Academy of Science and Technology Research (951156). Dr Kouichi Tamura is supported by a Research Fellowship of the Japan Society for the Promotion of Science for Young Scientists.
Received August 30, 1995; first decision October 9, 1995; accepted February 22, 1996.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Griendling KK, Murphy TJ, Alexander RW. Molecular biology of the renin-angiotensin system. Circulation. 1993;87:1816-1828.
2. Tamura K, Umemura S, Fukamizu A, Ishii M, Murakami K. Recent advances in the study of renin and angiotensinogen genes: from molecules to the whole body. Hypertens Res. 1995;18:7-18. [Medline] [Order article via Infotrieve]
3.
Dzau VJ, Re R. Tissue angiotensin
system in cardiovascular medicine: a paradigm
shift? Circulation. 1994;89:493-498.
4.
Walker WG, Whelton PK, Saito H, Russel RP, Herman
J. Relation between blood pressure and renin, renin substrate,
angiotensin II, aldosterone and urinary sodium
and potassium in 574 ambulatory subjects.
Hypertension. 1979;1:287-291.
5. Graham CMW, Harrap SB, Foy CJW, Holton DW, Edwards HE, Davidson HR, Connor JM, Lever AF, Fraser R. Abnormalities of glucocorticoid metabolism and the renin-angiotensin system: a four corners approach to the identification of genetic determinants of blood pressure. J Hypertens. 1992;10:473-482. [Medline] [Order article via Infotrieve]
6. Bloem LJ, Manatunga AK, Tewksbury DA, Pratt JH. The serum angiotensinogen concentration and variants of the angiotensinogen gene in white and black children. J Clin Invest. 1995;95:948-953.
7. Jeunemaitre X, Soubrier F, Kotelevtev YV, Lifton RP, Williams CS, Charru A, Hunt SC, Hopkins PN, Williams RR, Lalouel J-M, Corvol P. Molecular basis of human hypertension: role of angiotensinogen. Cell. 1992;71:169-180. [Medline] [Order article via Infotrieve]
8. Caufield M, Lavender P, Farrall M, Munroe P, Lawson M, Turner P, Clark AJL. Linkage of the angiotensinogen gene to essential hypertension. N Engl J Med. 1994;17:117-121.
9. Kimura S, Mullins JJ, Bunnemann B, Metzger R, Hilgenfeldt U, Zimmermann F, Jacob H, Fuxe K, Ganten D, Kaling M. High blood pressure in transgenic mice carrying the rat angiotensinogen gene. EMBO J. 1992;11:821-827. [Medline] [Order article via Infotrieve]
10.
Fukamizu A, Sugimura K, Takimoto E, Sugiyama F, Seo
M-S, Takahashi S, Hatae T, Kajiwara N, Yagami K, Murakami K.
Chimeric renin-angiotensin system demonstrates
sustained increase in blood pressure of transgenic mice carrying both
human renin and human angiotensinogen genes.
J Biol Chem. 1993;268:11617-11621.
11.
Yang G, Merrill DC, Thompson MW, Robillard JE, Sigmund
CD. Functional expression of the human
angiotensinogen gene in transgenic mice.
J Biol Chem. 1994;269:32497-32502.
12.
Tanimoto K, Sugiyama F, Goto Y, Ishida J, Takimoto E,
Yagami K, Fukamizu A, Murakami K.
Angiotensinogen-deficient mice with
hypotension. J Biol Chem. 1994;269:31334-31337.
13.
Kim H-S, Krege JH, Kluckman KD, Hagaman JR, Hodgin JB,
Best CF, Jennette JC, Coffman TM, Maeda N, Smithies O. Genetic
control of blood pressure and the angiotensinogen
locus. Proc Natl Acad Sci U S A. 1995;92:2735-2739.
14.
Bunkenburg B, Schnell C, Baum H-P, Cumin F, Wood
JM. Prolonged angiotensin II antagonism in
spontaneously hypertensive rats: hemodynamic and
biochemical consequences. Hypertension. 1991;18:278-288.
15.
Vicaut E, Hou X. Local
renin-angiotensin system in the microcirculation of
spontaneously hypertensive rats.
Hypertension. 1994;24:70-76.
16.
Wielbo D, Sernia C, Gyurko R, Phillips MI.
Antisense inhibition of hypertension in the spontaneously hypertensive
rat. Hypertension. 1995;25:314-319.
17.
Tomita N, Morishita R, Higaki J, Motokuni A, Nakamura
Y, Mikami H, Fukamizu A, Murakami K, Kaneda Y, Ogihara T.
Transient decrease in high blood pressure by in vivo transfer of
antisense oligonucleotides against rat
angiotensinogen. Hypertension. 1995;26:131-136.
18.
Yamakawa T, Tanaka S, Tamura K, Isoda F, Ukawa K,
Yamakura Y, Takanashi Y, Kiuchi Y, Umemura S, Ishii M, Sekihara
H. Wistar fatty rat is obese and spontaneously
hypertensive. Hypertension. 1995;25:146-150.
19.
Tokita Y, Franco-Saenz R, Reimann EM, Mulrow PJ.
Hypertension in the transgenic rat TGR(mRen-2)27 may be due to enhanced
kinetics of the reaction between mouse renin and rat
angiotensinogen. Hypertension. 1994;23:422-427.
20. Shimamoto K, Ishida H, Nakahashi Y, Nishitani T, Hosoda S, Yokoyama T, Tanaka S, Iimura O. A very sensitive direct radioimmunoassay system for plasma angiotensin II and its clinical application in various hypertensive diseases. Jpn Circ J. 1984;48:1228-1235. [Medline] [Order article via Infotrieve]
21.
Tamura K, Tanimoto K, Ishii M, Murakami K, Fukamizu
A. Proximal and core DNA elements are required for efficient
angiotensinogen promoter activation during adipogenic
differentiation. J Biol Chem. 1993;268:15024-15032.
22. Tamura K, Umemura S, Yamaguchi S, Iwamoto T, Kobayashi S, Fukamizu A, Murakami K, Ishii M. Mechanism of cAMP regulation of renin gene transcription by proximal promoter. J Clin Invest. 1994;94:1959-1967.
23. Chirgwin JM, Pryzbyla AE, MacDonald RJ, Rutter WJ. Isolation of biologically active ribonucleic acid from sources enriched in nuclease. Biochemistry. 1979;18:5294-5299. [Medline] [Order article via Infotrieve]
24.
Ohkubo H, Kageyama R, Ujihara M, Hirose T, Inayama S,
Nakanishi S. Cloning and sequence analysis of cDNA for
rat angiotensinogen. Proc Natl Acad Sci
U S A. 1983;80:2196-2200.
25.
Tso JY, Sun X-H, Kao T, Reece KS, Wu R.
Isolation and characterization of rat and human
glyceraldehyde-3-phosphate dehydrogenase cDNAs: genomic
complexity and molecular evolution of the gene. Nucleic
Acids Res. 1985;13:2485-2502.
26. Samni NJ, Swales JD, Brammar WJ. A widespread abnormality of renin gene expression in the spontaneously hypertensive rat: modulation in some tissues with the development of hypertension. Clin Sci. 1989;77:629-636.[Medline] [Order article via Infotrieve]
27. Okunishi H, Kawamoto T, Kurobe Y, Oka Y, Ishii K, Tanaka T, Miyazaki M. Pathogenetic role of vascular angiotensin-converting enzyme in the spontaneously hypertensive rat. Clin Exp Pharmacol Physiol. 1991;18:649-659. [Medline] [Order article via Infotrieve]
28.
Pratt RE, Zou WM, Naftilan AJ, Ingelfinger JR, Dzau
VJ. Altered sodium regulation of renal
angiotensinogen mRNA in the spontaneously hypertensive
rat. Am J Physiol. 1989;256:F469-F474.
29.
Yongue BG, Angulo JA, McEwen BS, Myers MM. Brain
and liver angiotensinogen messenger RNA in genetic
hypertensive and normotensive rats.
Hypertension. 1991;17:485-491.
30. Eggena P, Barrett JD. Regulation and functional consequences of angiotensinogen gene expression. J Hypertens. 1992;10:1307-1311. [Medline] [Order article via Infotrieve]
31. Deschepper CF. Angiotensinogen: hormonal regulation and relative importance in the generation of angiotensin II. Kidney Int. 1994;46:1561-1563. [Medline] [Order article via Infotrieve]
32. Brasier AR, Li J, Copland A. Transcriptional factors modulating angiotensinogen gene expression in hepatocytes. Kidney Int. 1994;46:1564-1566. [Medline] [Order article via Infotrieve]
33.
Klett C, Ganten D, Hellmann W, Kaling M, Ryffel GU,
Weimar-Ehl T, Hackenthal E. Regulation of hepatic
angiotensinogen synthesis and secretion by steroid
hormones. Endocrinology. 1992;130:3660-3668.
34.
Klett C, Nobiling R, Gierschik P, Hackenthal E.
Angiotensin II stimulates the synthesis of
angiotensinogen in hepatocytes by inhibiting
adenylylcyclase activity and stabilizing angiotensin
mRNA. J Biol Chem. 1993;268:25095-25107.
35. Jackson RJ, Standart N. Do the poly(A) tail and 3' untranslated region control mRNA translation? Cell. 1990;62:15-24. [Medline] [Order article via Infotrieve]
36. Wolffe AP, Tata JR. Primary culture, cellular stress and differentiated function. FEBS Lett. 1984;176:8-15. [Medline] [Order article via Infotrieve]
37.
Lodwick D, Kaiser MA, Harris J, Cumin F, Vincent M,
Samani NJ. Analysis of the role of
angiotensinogen in spontaneous hypertension.
Hypertension. 1995;25:1245-1251.
38. Phillips MI, Kimura BC. Brain angiotensin in the developing spontaneously hypertensive rat. J Hypertens. 1988;6:607-612. [Medline] [Order article via Infotrieve]
39.
Campbell DJ, Duncan A-M, Kladis A, Harrap SB.
Angiotensin peptides in spontaneously hypertensive and
normotensive Donryu rats. Hypertension. 1995;25:928-934.
40. Naftilan AJ, Zuo WM, Ingelfinger JR, Ryan TJ Jr, Pratt RE, Dzau VJ. Localization and differential regulation of angiotensinogen mRNA expression in the vessel wall. J Clin Invest. 1991;87:1300-1311.
41.
Shiota N, Miyazaki M, Okunishi H. Increase of
angiotensin converting enzyme gene expression in the
hypertensive aorta. Hypertension. 1992;20:168-174.
42.
Vicaut E, Hou X. Arteriolar constriction and
local renin-angiotensin system in rat
microcirculation. Hypertension. 1993;21:491-497.
43. Rettig R, Folberth C, Kopf D, Stauss H, Unger T. Role of the kidney in the pathogenesis of primary hypertension. Clin Exp Hypertens A. 1990;12:957-1002. [Medline] [Order article via Infotrieve]
44. Norman RA Jr, Enobakhare JA, DeClue JW, Douglas BH, Guyton AC. Arterial pressure-urinary output relationship in hypertensive rats. Am J Physiol. 1978;234:R98-R103.
45. Harrap SB, Doyle AE. Genetic co-segregation of renal haemodynamics and blood pressure in the spontaneously hypertensive rat. Clin Sci. 1988;74:63-69. [Medline] [Order article via Infotrieve]
46.
Nørrelund H, Christensen KL, Samani NJ, Kimber P,
Mulvany MJ, Korsgaard N. Early narrowed afferent arteriole is a
contributor to the development of hypertension.
Hypertension. 1994;24:301-308.
47. Mitchell KD, Braam B, Navar LG. Hypertensinogenic mechanisms mediated by renal actions of renin-angiotensin system. Hypertension. 1992;19(suppl I):I-18-I-27.
48.
Reinhart GA, Lohmeier TE, Hord CE Jr. Hypertension
induced by chronic renal adrenergic stimulation is
angiotensin dependent. Hypertension. 1995;25:940-949.
49.
Campbell DJ, Lawrence AC, Towrie A, Kladis A, Valentijn
AJ. Differential regulation of angiotensin peptide
levels in plasma and kidney of the rat.
Hypertension. 1991;18:763-773.
50. Schunkert H, Ingelfinger JR, Hirsch AT, Tang S-S, Litwin SE, Talsness CE, Dzau VJ. Evidence for tissue-specific activation of renal angiotensinogen mRNA expression in chronic stable experimental heart failure. J Clin Invest. 1992;90:1523-1529.
51.
Morishita R, Higaki J, Okunishi H, Nakamura F, Nagano
M, Mikami H, Ishii K, Miyazaki M, Ogihara T. Role of tissue
renin angiotensin system in two-kidney, one-clip
hypertensive rats. Am J Physiol. 1993;264:F510-F514.
52.
Kim S, Tokuyama M, Hosoi M, Yamamoto K. Adrenal
and circulating renin-angiotensin system in
stroke-prone hypertensive rats.
Hypertension. 1992;20:280-291.
53.
Bader M, Zhao Y, Sander M, Lee MA, Bachmann J, Bohm M,
Djavidani B, Peters J, Mullins JJ, Ganten D. Role of tissue
renin in the pathophysiology of hypertension in TGR(mREN2)27
rats. Hypertension. 1992;19:681-686.
54.
Frederick RC, Kalm BB, Peach MJ, Flier JS.
Tissue specific nutritional regulation of angiotensinogen
in adipose tissue. Hypertension. 1992;19:339-344.
55.
Bruckschlegel G, Holmer SR, Jandeleit K, Grimm D,
Muders F, Kromer EP, Riegger GAJ, Schunkert H. Blockade of the
renin-angiotensin system in cardiac
pressure-overload hypertrophy in rats.
Hypertension. 1995;25:250-259.
56.
von Lutterotti N, Catanzaro DF, Sealey JE, Laragh
JH. Renin is not synthesized by cardiac and extrarenal vascular
tissues: a review of experimental evidence.
Circulation. 1994;89:458-470.
57. Sadoshima J, Xu Y, Slayter HS, Izumo S. Autocrine release of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro. Cell. 1993;75:977-984. [Medline] [Order article via Infotrieve]
58.
Baker KM, Chernin MI, Wixson SK, Aceto JF.
Renin-angiotensin system involvement in
pressure-overload cardiac hypertrophy in rats.
Am J Physiol. 1990;259:H324-H332.
59.
Rakugi H, Jacob HJ, Krieger JE, Ingelfinger JR, Pratt
RE. Vascular injury induces angiotensinogen gene
expression in the media and neointima.
Circulation. 1993;87:283-290.
60.
Ishigami T, Umemura S, Iwamoto T, Tamura K, Hibi K,
Yamaguchi S, Nyui N, Kimura K, Miyazaki N, Ishii M. Molecular
variant of angiotensinogen gene is associated with
coronary atherosclerosis.
Circulation. 1995;91:951-954.
This article has been cited by other articles:
 |
|
 |
|
  A.-i. Shigenaga, K. Tamura, H. Wakui, S.-i. Masuda, K. Azuma, Y. Tsurumi-Ikeya, M. Ozawa, M. Mogi, M. Matsuda, K. Uchino, et al. Effect of Olmesartan on Tissue Expression Balance Between Angiotensin II Receptor and Its Inhibitory Binding Molecule Hypertension, October 1, 2008; 52(4): 672 - 678. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Xiang, J. Kong, S. Chen, L.-P. Cao, G. Qiao, W. Zheng, W. Liu, X. Li, D. G. Gardner, and Y. C. Li Cardiac hypertrophy in vitamin D receptor knockout mice: role of the systemic and cardiac renin-angiotensin systems Am J Physiol Endocrinol Metab, January 1, 2005; 288(1): E125 - E132. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. O'Regan, C. J. Kenyon, J. R. Seckl, and M. C. Holmes Glucocorticoid exposure in late gestation in the rat permanently programs gender-specific differences in adult cardiovascular and metabolic physiology Am J Physiol Endocrinol Metab, November 1, 2004; 287(5): E863 - E870. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Serazin, M.-N. Dieudonne, M. Morot, P. de Mazancourt, and Y. Giudicelli cAMP-positive regulation of angiotensinogen gene expression and protein secretion in rat adipose tissue Am J Physiol Endocrinol Metab, March 1, 2004; 286(3): E434 - E438. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Naito, T. Tsujino, Y. Fujioka, M. Ohyanagi, and T. Iwasaki Augmented Diurnal Variations of the Cardiac Renin-Angiotensin System in Hypertensive Rats Hypertension, December 1, 2002; 40(6): 827 - 833. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Dalla Libera, B. Ravara, A. Angelini, K. Rossini, M. Sandri, G. Thiene, G. Battista Ambrosio, and G. Vescovo Beneficial Effects on Skeletal Muscle of the Angiotensin II Type 1 Receptor Blocker Irbesartan in Experimental Heart Failure Circulation, May 1, 2001; 103(17): 2195 - 2200. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M Sharma and S. Engeli The renin-angiotensin system in obesity hypertension Journal of Renin-Angiotensin-Aldosterone System, March 1, 2001; 2(1_suppl): S114 - S119. [PDF]
|
|
|
|
|
|
V. Serazin-Leroy, M. Morot, P. de Mazancourt, and Y. Giudicelli Androgen regulation and site specificity of angiotensinogen gene expression and secretion in rat adipocytes Am J Physiol Endocrinol Metab, December 1, 2000; 279(6): E1398 - E1405. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Engeli, R. Negrel, and A. M. Sharma Physiology and Pathophysiology of the Adipose Tissue Renin-Angiotensin System Hypertension, June 1, 2000; 35(6): 1270 - 1277. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Reaux, M. C. Fournie-Zaluski, C. David, S. Zini, B. P. Roques, P. Corvol, and C. Llorens-Cortes Aminopeptidase A inhibitors as potential central antihypertensive agents PNAS, November 9, 1999; 96(23): 13415 - 13420. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Zicha and J. Kunes Ontogenetic Aspects of Hypertension Development: Analysis in the Rat Physiol Rev, October 1, 1999; 79(4): 1227 - 1282. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. L. Davisson, G. Yang, T. G. Beltz, M. D. Cassell, A. K. Johnson, and C. D. Sigmund The Brain Renin-Angiotensin System Contributes to the Hypertension in Mice Containing Both the Human Renin and Human Angiotensinogen Transgenes Circ. Res., November 16, 1998; 83(10): 1047 - 1058. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Tamura, S. Umemura, N. Nyui, K. Hibi, T. Ishigami, M. Kihara, Y. Toya, and M. Ishii Activation of angiotensinogen gene in cardiac myocytes by angiotensin II and mechanical stretch Am J Physiol Regulatory Integrative Comp Physiol, July 1, 1998; 275(1): R1 - R9. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Ishigami, S. Umemura, K. Tamura, K. Hibi, N. Nyui, M. Kihara, M. Yabana, Y. Watanabe, Y. Sumida, T. Nagahara, et al. Essential Hypertension and 5' Upstream Core Promoter Region of Human Angiotensinogen Gene Hypertension, December 1, 1997; 30(6): 1325 - 1330. [Abstract] [Full Text]
|
|
|
|
|
|
N. Nyui, K. Tamura, S. Yamaguchi, M. Nakamaru, T. Ishigami, M. Yabana, M. Kihara, H. Ochiai, N. Miyazaki, S. Umemura, et al. Tissue Angiotensinogen Gene Expression Induced by Lipopolysaccharide in Hypertensive Rats Hypertension, October 1, 1997; 30(4): 859 - 867. [Abstract] [Full Text]
|
|
|
|
 |
|
 K. Tamura, Y. E. Chen, M. Lopez-Ilasaca, L. Daviet, N. Tamura, T. Ishigami, M. Akishita, I. Takasaki, Y. Tokita, R. E. Pratt, et al. Molecular Mechanism of Fibronectin Gene Activation by Cyclic Stretch in Vascular Smooth Muscle Cells J. Biol. Chem., October 27, 2000; 275(44): 34619 - 34627. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||