Increased Brain Transcription Factor Expression by Angiotensin in Genetic Hypertension
A stimulated brain renin-angiotensin system has been implicated in genetic hypertension. We compared the effects of an intracerebroventricular injection of angiotensin II (100 ng) on the expression of inducible transcription factors c-Fos, c-Jun, and Krox-24 in the brain of spontaneously hypertensive rats (SHR), in Wistar rats with nephrogenic hypertension induced by aortic banding, and in normotensive Wistar-Kyoto and Wistar rats immunohistochemically. Generally, the angiotensin II–induced transcription factor expression was strictly confined to four distinct forebrain areas: the subfornical organ, median preoptic area, paraventricular nucleus, and supraoptic nucleus. In SHR, the angiotensin II–induced c-Fos and c-Jun expressions were significantly enhanced compared with those in normotensive control strains as well as in secondary hypertensive Wistar rats. Krox-24 expression in the subfornical organ, median preoptic area, and paraventricular nucleus of SHR was also significantly increased compared with that in all control strains. In the supraoptic nucleus, significant differences could be discriminated between SHR and secondary hypertensive Wistar rats. Injection of isotonic saline or arginine vasopressin (100 ng) as controls did not induce any expression of c-Fos, c-Jun, or Krox-24. Our findings demonstrate an enhanced sensitivity of SHR to angiotensin II–induced transcription factor expression in distinct brain areas involved in central blood pressure and osmotic control that is independent of blood pressure.
During the last two decades, the contribution of the brain renin-angiotensin system to the central control of BP and body volume homeostasis has been intensively studied. A controversial hypothesis that has emerged from these studies holds that brain angiotensin peptides are involved in pathogenetic mechanisms leading to and maintaining elevated BP in genetic forms of hypertension such as the SHR (for review, see References 1 through 3). Evidence in support of this hypothesis has been obtained with pharmacological, biochemical, and molecular biological methods. Most recently, it was reported that in SHR, central administration of antisense oligonucleotides to the AT1 receptor mRNA and angiotensinogen mRNA was followed by a long-lasting BP reduction.4
These recent findings together with our widened knowledge about the localization and function of angiotensin receptor subtypes in the brain as well as the role of Ang II in neuroplastic processes5 have newly stirred up questions as to the possible long-term mechanisms by which a stimulated brain renin-angiotensin system could contribute to genetic hypertension.
The basis for lasting effects of Ang II is an activation of Ang II receptors with subsequent information transfer into the nucleus and alterations in gene transcription. Within the control of gene transcription, ITFs play a crucial role by regulating the transcription of other genes via binding to specific target sequences in the respective promoters.6 7 By expression of ITFs, which are usually not detectable during the absence of intentional stimuli,8 transsynaptic excitation of neurons can efficiently change effector gene expression with alterations in the neuronal program.9 10 11
Recently, we have shown that intracerebroventricular injections of Ang II induced a complex temporospatial expression pattern of several ITFs of the Fos, Jun, and Krox families in the brain of conscious normotensive male Wistar rats.5 12 This expression was dose dependent, mediated by AT1 receptors, and restricted to four specific regions of the forebrain: the SFO, MnPO, PVN, and SON of the hypothalamus, that is, brain areas associated with volume homeostasis and BP control. In the present study, we examined whether the Ang II–induced expression of three ITFs—c-Fos, c-Jun, and Krox-24 (zinc finger-binding protein clone 268 [Zif 268], early growth response-gene 1 [egr-1], nerve growth factor-inducible gene A [NGFI-A])—in the brain shows any differences in SHR compared with normotensive WKY and Wistar controls and controls with secondary hypertension caused by aortic banding (WIab). Additionally, in two other groups of SHR and Wistar rats, we confirmed the involvement of AT1 receptors in the Ang II–induced ITF expression. We included experiments with a peptide of a similar molecular weight, AVP, to determine the specificity of the Ang II–induced effects. Our results in SHR reveal specific alterations of responsiveness on the level of transcription in distinct brain nuclei involved in central cardiovascular control.
Rat Strains and Aortic Banding
Wistar rats (280 to 300 g, 12 weeks old; n=51) (obtained from Dr Karl Thomae GmbH), WKY (280 to 300 g, 12 weeks old; n=18), and SHR (240 to 260 g, 12 weeks old; n=33) (both obtained from Möllegard, Skensved, Denmark) were kept under standard conditions with respect to food, humidity, and light periodicity. All experiments were performed in accordance with institutional guidelines.
For induction of nephrogenic hypertension in Wistar rats, aortic banding was performed as described previously.13 Briefly, the abdomen of fasted rats was opened with rats under hexabarbital anesthesia (200 mg/kg IP), and the abdominal aorta was exposed between the renal arteries. A blunt cannula (0.9×40 mm) was placed longitudinally on the aorta, and the aorta and cannula were tied with a silk thread. Removal of the cannula left an aortic lumen that corresponded to the diameter of the cannula. The rats were allowed a 2-week recovery period before implantation of the intracerebroventricular cannulas.
Mean arterial BP was measured in conscious rats via a chronic intra-arterial catheter (PP10 in PP50, Neolab) placed in the left carotid artery 3 days before the measurement with rats under chloralhydrate anesthesia (400 mg/kg IP). We had previously verified that implantation of the carotid catheter had no effect on ITF levels in the brain. BP measurements in all groups were performed 2 days before the acute experiment.
For intracerebroventricular injections, chronic cannulas (PP20, Neolab) were implanted into the right lateral brain ventricle with rats under chloralhydrate anesthesia (400 mg/kg IP). Rats were housed individually during a 1-week postoperative period to minimize stress-induced expression of ITFs and were handled daily during this time.
All intracerebroventricular injections were made between 8 and 11 am in conscious rats to avoid interference of circadian rhythms or anesthesia with ITF expression. Rats of each group were randomly allocated to intracerebroventricular injections of 100 ng Ang II (n=8), 100 ng AVP (n=5), or isotonic saline (n=5). Two additional groups of SHR and Wistar rats (n=15 each) were pretreated with 5 μg (Wistar) or 10 μg (SHR) losartan ICV 5 minutes before injection of Ang II (100 ng, n=5); controls for this experiment included treatment with a combination of losartan (5 μg [Wistar], 10 μg [SHR]) followed by isotonic saline (n=5 for each group) as well as a combination of isotonic saline and Ang II (100 ng, n=5 for each group). The injection volume was 5 μL (1 μL Ang II, AVP, or losartan solution flushed with 4 μL isotonic saline or 5 μL isotonic saline as a control). The doses of Ang II, AVP, and losartan were selected on the basis of previous experiments.5 Ninety minutes after intracerebroventricular injection, rats were deeply anesthetized with diethylether and perfused intracardially with phosphate-buffered saline followed by 4% paraformaldehyde solution for fixation of brain tissue. Brains were removed and postfixed for 24 hours in 4% paraformaldehyde (4°C); thereafter, the tissue was incubated in 30% sucrose for cryoprotection (3 days, 4°C).
Ang II (Bachem) and AVP (Boehringer) were stored in stock solutions at −20°C. Dilutions in isotonic NaCl were prepared on the day of the experiment. Losartan was a generous gift from Dr R.D. Smith (DuPont Merck Pharmaceutical Co); it was dissolved in 0.9% NaCl and stored at −20°C until use.
Coronal, cryostat-cut brain sections (50 μm) were processed free-floating for immunocytochemistry. Incubation with the primary antisera was followed by immunostaining with the conventional avidin-biotin complex peroxidase reaction as described previously.14 The dilutions of the antisera were as follows: anti–c-Fos, 1:25 000; anti–c-Jun, 1:30 000; and anti–Krox-24, 1:4000. Specificity and generation of the antisera have been described in detail elsewhere.15 16 For each group, one (SFO) or two (MnPO, PVN, SON) corresponding sections of each specifically labeled area were photographed.
Data represent mean±SD. Stained neurons were counted on the photographs by two investigators in a blinded fashion. Average numbers and SDs were calculated per area and per group. Statistical analysis comparing Ang II–induced ITF changes in each brain nucleus between experimental groups was performed with ANOVA followed by the Student-Newman-Keuls test. A value of P<.05 was accepted as significant.
BP values in SHR and WIab were comparably elevated and clearly distinct from those in normotensive strains. The data for each group are summarized in Table 1⇓.
Expression of ITFs
The immunoreactivity for c-Fos, c-Jun, and Krox-24 was exclusively nuclear and restricted to neurons in four specific brain regions: the SFO, MnPO, PVN, and SON. In the ependyma of the lateral ventricle, a nonspecific expression was visible after injection of Ang II as well as after injection of isotonic saline.
ITF expression in NaCl–treated controls of all groups, SHR, WKY, Wistar, and WIab, was similar to basal levels of untreated rats as described previously.5 In the four brain regions mentioned above, no stained neurons (for c-Fos and c-Jun) or only single neurons (Krox-24) were found after intracerebroventricular injection of isotonic saline. This finding corresponded exactly to basal levels of untreated rats.5 Also, in other brain regions that showed no specific ITF expression after treatment with Ang II (100 ng), such as the cortex, isotonic saline did not induce any ITF expression above basal levels.
Ang II (100 ng ICV) induced the expression of the ITF c-Fos in the four above-mentioned brain regions of SHR, WKY, Wistar, and WIab rats (Fig 1⇓). Intracerebroventricular injections of NaCl did not induce any c-Fos expression that was different from the basal expression of single scattered cells in these regions.
The Ang II–induced expression of c-Fos was significantly increased in SHR compared with WKY, Wistar, and WIab rats in all brain regions except the PVN, where SHR values were clearly elevated compared with those in WKY and Wistar rats but not significantly so because of high variability in the SHR group; values in WIab rats were significantly different from those in SHR. The c-Fos expression in WIab rats did not differ from that in normotensive rats (Table 2⇓ and Fig 2⇓). In other regions of the forebrain, such as the olfactory cortex or the nucleus accumbens, all rats exhibited c-Fos expression patterns that did not differ from basal levels of untreated rats.
c-Jun showed a more differential pattern of expression after intracerebroventricular injection of Ang II. All strains revealed an Ang II–induced expression of c-Jun in the SFO, MnPO, and PVN. In addition, SHR and WKY also exhibited c-Jun immunoreactivity in the SON (Fig 3⇓), whereas Wistar and WIab rats did not express c-Jun in this region. Since c-Jun was expressed in other areas of Wistar and WIab rat brains, its absence in the SON suggests a strain-specific regulation in this region.
c-Jun expression was significantly higher in all four brain areas of SHR than in those of WKY, Wistar, and WIab rats. No such differences could be detected in basally labeled regions such as the hippocampus or cortex. NaCl-treated control rats did not show any c-Jun expression above basal levels in any of these areas (Table 2⇑).
Krox-24 was expressed in all rat strains in the SFO, MnPO, PVN, and SON after intracerebroventricular injection of Ang II, whereas NaCl-treated controls showed only basal expression in a few scattered neurons. SHR exhibited Krox-24 expression in the SFO, MnPO, and PVN that was significantly increased compared with that of WKY, Wistar, and WIab rats (Fig 4⇓). In contrast, for the SON, Krox-24 expression levels between SHR and WIab rats were significantly different but not between SHR and WKY or SHR and Wistar rats; all strains showed a very high number of Krox-24–immunoreactive neurons after Ang II treatment (Table 2⇑).
Generally, in each of the four brain areas, the number of neurons that expressed Krox-24 in response to Ang II was much higher than the number of neurons that expressed c-Fos or c-Jun. In areas that exhibit a constitutive level of Krox-24–immunoreactive cells, such as the hippocampus, no differences between SHR and the control strains were observed (Fig 5⇓).
Apart from the differences in the four specific brain regions mentioned above, differential expression patterns could not be detected among the four rat groups or between NaCl-treated control and untreated rats.
Intracerebroventricular injection of 100 ng AVP did not induce any expression of c-Fos, c-Jun, or Krox-24 in the MnPO, SFO, PVN, or SON of SHR, WKY, Wistar, or WIab rats.
AT1 Receptor Blockade With Losartan
Intracerebroventricular pretreatment of Wistar rats with the AT1 receptor antagonist losartan at a dose of 5 μg inhibited the Ang II–induced expression of c-Fos, c-Jun, and Krox-24 in all brain regions down to basal levels of NaCl-treated or untreated rats as described before.5 Control rats treated with 5 μg losartan followed by injection of isotonic saline did not exhibit any stained neurons in the specific regions, showing that losartan alone is not capable of inducing ITF expression. Control rats treated with a combination of isotonic saline and Ang II (100 ng) showed the same expression pattern with regard to the number of stained neurons and the regions of expression as in rats treated with Ang II (100 ng) alone.
In SHR, 10 μg losartan inhibited the Ang II (100 ng)–induced expression of c-Fos, c-Jun, and Krox-24 to basal levels. Again, losartan (10 μg) alone did not induce any ITF expression, and a combination of isotonic saline and Ang II (100 ng) yielded a result similar to that obtained with Ang II (100 ng) alone (Table 3⇓).
The SHR strain used in the present study has been shown to respond to an intracerebroventricular injection of Ang II with a BP elevation that is higher than the respective elevation in normotensive rats,17 pointing to a role of Ang II in the hypertensive status of these rats. Here, we demonstrate that these genetically hypertensive rats exhibit significantly increased numbers of cells immunoreactive for c-Fos, c-Jun, and Krox-24 expression after an intracerebroventricular injection of Ang II in distinct areas of the forebrain compared with normotensive control rats or rats with induced nephrogenic hypertension.
We have shown before that Ang II induces ITF expression when applied intracerebroventricularly in doses between 1 and 100 ng, underlining the physiological importance of Ang II–induced transcription factor expression in the brain.5 The dose of 100 ng used here ensures that the effects of Ang II in the different strains are clearly differential and comparable to other effects described in earlier studies.18 19
Concerning the number of ITF-immunoreactive cells after Ang II injection in each region, we observed a high homogeneity between normotensive and secondary hypertensive rats, with only slight differences of individual ITFs in single regions. The fact that the level of Ang II–induced ITF expression in Wistar rats with induced hypertension was within the range of that of normotensive Wistar rats and WKY indicates that the elevated BP by itself is not responsible for an increased Ang II–induced ITF expression. Thus, the increased sensitivity to Ang II in SHR appears to be genetically determined.
The present study reveals some common features of the Ang II–induced expression of ITFs in the brain of different rat strains. In all strains, the Ang II–induced expression was exclusively nuclear and restricted to neurons. All rats expressed c-Fos, c-Jun, and Krox-24 exclusively in the same four distinct brain regions: the SFO, MnPO, PVN, and SON. This is remarkable because Krox-24 belongs to another group of ITFs than c-Fos and c-Jun, the so-called zinc-finger proteins; it binds to a different consensus sequence on the DNA, the early growth response (egr) site; and it has different transcriptional activity.20
Ang II evoked a strong expression of Krox-24 in the SON that was rather similar in all four groups investigated. The lack of a higher expression level in SHR might be due to a particular threshold of Krox-24 inducibility in the SON, with a near-maximal expression occurring already in normotensive rats. Such a low induction threshold of Krox-24 has recently been demonstrated in hippocampal and cortical neurons, where Krox-24 expression is governed by mere synaptic activity via N-amino-d-aspartate receptors.21 22
Generally, the number of Krox-24–immunoreactive cells surpassed that of c-Fos– or c-Jun–immunoreactive cells, indicating that the stimulus threshold for this factor was lower than that of the other ITFs.
In NaCl-injected control rats of normotensive and hypertensive groups, the expression of c-Fos, c-Jun, and Krox-24 did not differ among the groups in this study or between untreated Wistar and Sprague-Dawley rats as described previously.5 8 Furthermore, NaCl injection did not induce ITF expression in the areas that respond to Ang II. These findings indicate that neither the genetic background of SHR nor the nephrogenically induced hypertension alters the threshold of intrinsic or stimulus-induced ITF expression. This holds true also for Krox-24, which might be particularly sensitive to alterations in its transcription control because of its low induction threshold. A peptide with a similar molecular weight, AVP, did not induce any expression of c-Fos, c-Jun, or Krox-24 in any of the four Ang II–stimulated regions, showing that the observed effects are not due to nonspecific peptide interactions.
Gyurko et al4 recently used antisense oligonucleotides to study the contribution of Ang II and its receptors to hypertension in SHR: intracerebroventricular injections of antisense oligonucleotides against angiotensinogen mRNA reduced angiotensinogen levels in the brain stem as well as BP. Antisense inhibition of the AT1 receptor mRNA also decreased BP and reduced expression of AT1 receptors in the PVN and areas adjacent to the anterior third ventricle.
The regions of Ang II–induced ITF expression have been shown to be important for BP regulation in SHR and normotensive rats. Notably, Eilam and coworkers23 demonstrated that hypertension could be induced in WKY by transplantation of hypothalamic tissue from genetically hypertensive SHR. Transplanted rats showed not only an increase in systolic BP but also behavioral changes similar to those of native SHR strains. In subsequent studies, the same authors were able to attribute the changes in BP to the rostral part of the hypothalamus, which contains the PVN and SON, whereas transplantations of the caudal part of the hypothalamus had no such effects.24
Two types of Ang II receptors, AT1 and AT2, have been localized in the brain of adult rats. AT1 receptors were present in brain regions such as the nucleus of the solitary tract; the suprachiasmatic, supraoptic, and paraventricular nuclei; the median preoptic area; the subfornical organ; the dentate gyrus; and the area postrema. Areas such as the superior colliculus or the cerebellar cortex expressed both subtypes, and regions such as the lateral septal or ventral thalamic area, the locus coeruleus, or the inferior olive contained only AT2 receptors.25 26 The picture is even more complicated by the finding that the two angiotensin receptors each display heterogeneous subtypes: the AT1A subtype is localized predominantly in the hypothalamus, and the AT1B subtype predominates in the circumventricular organs.27 In SHR, both AT1A and AT1B receptor mRNAs are elevated in hypothalamus and brain stem compared with levels in WKY.28 Interestingly, in the pituitary, AT1B receptors are downregulated by estrogen29 ; this might also be true in the circumventricular organs.27 AT2 receptors also appear to be distributed heterogeneously: AT2A receptors are located, for instance, in the ventral thalamic area and AT2B receptors in the inferior olive.30
As shown before5 and demonstrated here in SHR and Wistar rats, the Ang II–induced expression of ITFs in the brain is mediated by AT1 receptors. It is plausible that the higher density of AT1 receptors in the brain of SHR contributes to elevated Ang II–induced levels of ITFs in these rats.
The enhanced Ang II–induced expression of ITFs in the brain of SHR, which includes not only the number of stained cells but also the amount of ITF expression in a given neuron (shown by the fact that the number of light- or medium-brown nuclei diminishes but the number of dark-brown nuclei increases), influences the regulation of target genes. The regulatory potency of ITF dimers depends not only on the partners that form them but also on the composition of the binding sequence itself and of the DNA region flanking the consensus sequence, since these compositions influence the binding affinity between binding sites and ITF dimers. Thus, ITFs present in higher amounts in a neuron may bind to promoters with low-affinity sites for ITFs and influence expression of the respective genes, whereas ITFs present in low amounts are more likely to regulate genes with high-affinity consensus sequences. The consequence is an altered set of addressed target genes in neurons with increased ITF expression. In vitro experiments have demonstrated that transcription factors enhance their transcriptional operations with increasing concentration,15 for example, by improved competition for dimerization or DNA binding. The recruitment of more neurons for ITF expression after a defined stimulus as seen here in SHR may also have consequences on signal transduction, for example, in convergent signaling pathways where the threshold for transmission of excitations may be reached more easily.
The exact nature of the target genes that are addressed as a consequence of Ang II–induced ITF expression remains to be elucidated, but there are a number of promising candidates for further studies. The genes for angiotensinogen and for the AT1 receptor both contain activator protein-1 (AP-1) recognition sites for ITF dimers of the Fos and Jun families or sites that may be addressed by AP-1 proteins interacting with other transcriptionally active proteins, such as nuclear factor-κB.31 32 As mentioned before, estrogen is supposed to take part in the regulation of AT1 receptors in the circumventricular organs. Glucocorticoid response elements and steroid receptors have been described to interact with AP-1 proteins in several other systems. Thus, AP-1 proteins could, on one hand, participate in regulatory circuits of the brain renin-angiotensin system by regulating AT1 receptor numbers via binding to AP-1 directly, or, on the other hand, interact with estrogen receptors to influence AT1 transcription.
Another potential target gene for an Ang II–induced ITF activation is the gene for AVP, which contains a cAMP response element site in its 5′ promoter region.33 We have recently been able to colocalize AVP and c-Fos/c-Jun in the same cells (A.B., unpublished data, 1996); thus, the resynthesis of AVP in the magnocellular neurons of these areas may be controlled by ITF.
Other AP-1–controlled genes in the brain include the gene for nerve growth factor and the glial fibrillary acid protein.34 35 Although these proteins are not thought to contribute directly to the pathogenesis of hypertension, they may take part in neuroplastic processes leading to morphological or physiological changes in the central nervous system, which may finally have an effect on central BP control.
Selected Abbreviations and Acronyms
|Ang II||=||angiotensin II|
|AT1, AT2||=||angiotensin type 1, type 2 (receptor)|
|ITF||=||inducible transcription factor|
|MnPO||=||median preoptic area|
|PVN||=||paraventricular nucleus of the hypothalamus|
|SHR||=||spontaneously hypertensive rat(s)|
|WIab||=||Wistar rats with aortic banding|
This study was supported by a group grant from the Deutsche Forschungsgemeinschaft (DFG) (Zi 110/22-2). Annegret Blume was a recipient of a training grant from the DFG (Graduiertenkolleg “Molekulare und zelluläre Neurobiologie,” University of Heidelberg).
- Received July 7, 1996.
- Revision received August 10, 1996.
- Revision received September 3, 1996.
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