(Hypertension. 2000;36:282.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Effect of Bosentan on NF-
B, Inflammation, and Tissue Factor in Angiotensin II–Induced End-Organ Damage
From Franz Volhard Clinic, Medical Faculty of the Charité, Humboldt University of Berlin, Germany (D.N.M., E.M.A.M., F.S., J.-K.P., R.D., E.G., W.S., F.C.L.); the Institute of Biomedicine, University of Helsinki, Finland (E.M.A.M.); Max Delbrück Center for Molecular Medicine, Berlin, Germany (D.G.); Medizinische Hochschule Hannover, Hannover, Germany (H.H.); and Hoffmann-La Roche, Basel, Switzerland (V.B., B.-M.L.).
Correspondence to Friedrich C. Luft, Franz Volhard Clinic, Wiltberg Strasse 50, 13125 Berlin, Germany. E-mail luft{at}fvk-berlin.de
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Abstract |
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Abstract—Reports on the effectiveness of endothelin receptor blockers in angiotensin (Ang) II–induced end-organ damage are conflicting, and the mechanisms involved are uncertain. We tested the hypothesis that endothelin (ET)A/B receptor blockade with bosentan (100 mg/kg by gavage after age 4 weeks) ameliorates cardiac and renal damage by decreasing inflammation in rats harboring both human renin and angiotensinogen genes (dTGR). Furthermore, we elucidated the effect of bosentan on tissue factor (TF), which is a key regulator of the extrinsic coagulation cascade. We compared bosentan with hydralazine (80 mg/L in the drinking water for 3 weeks) as a blood pressure control. Untreated dTGR featured hypertension, focal necrosis in heart and kidney, and a 45% mortality rate (9 of 20) at age 7 weeks. Compared with Sprague-Dawley controls, both systolic blood pressure and 24-hour albuminuria were increased in untreated dTGR (203±8 versus 111±2 mm Hg and 67.1±8.6 versus 0.3±0.06 mg/d at week 7, respectively). Bosentan and hydralazine both reduced blood pressure and cardiac hypertrophy. Mortality rate was markedly reduced by bosentan (1/15) and partially by hydralazine (4/15). However, only bosentan decreased albuminuria and renal injury. Untreated and hydralazine-treated dTGR showed increased nuclear factor (NF)-
B and AP-1 expression in the kidney and heart; the p65 NF-B
subunit was increased in the endothelium, vascular
smooth muscles cells, infiltrating cells, glomeruli, and tubules. In
the heart and kidney, ETA/B receptor blockade inhibited
NF-B and AP-1 activation compared with hydralazine
treatment. Macrophage infiltration, ICAM-1 expression, and the
integrin expression on infiltrating cells were markedly reduced. Renal
vasculopathy was accompanied by increased tissue factor expression on
macrophages and vessels of untreated and
hydralazine-treated dTGR, which was markedly reduced by
bosentan. Thus, ETA/B receptor blockade inhibits NF-B
and AP-1 activation and the NF-B– and/or AP-1–regulated genes
ICAM-1, VCAM-1, and TF, independent of
blood pressure–related effects. We conclude that Ang II–induced
NF-B and AP-1 activation and subsequent inflammation and coagulation
involve at least in part the ETA/B receptors.
Key Words: angiotensin I • endothelin • genes • albuminuria • renin-angiotensin system
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Introduction |
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The development and progression of malignant, hypertension-induced, end-organ damage is incompletely understood; however, vascular inflammatory responses, extracellular matrix protein accumulation, and thrombosis in small vessels are all involved.1 2 3 Angiotensin (Ang) II, the key effector of the local and circulating renin-angiotensin system, plays a central role.3 4 Recently, Ang II was shown to be a powerful stimulator of endothelin (ET-1) synthesis and release in vascular smooth muscle and endothelial cells.5 6 7 8 Furthermore, Ang II–induced tissue ET-1 fosters vascular hypertrophy.9 10 The importance of ET-1 in cardiovascular disease has recently been reviewed.11 Ang II can activate the nuclear transcription factor NF-
B. NF-B is primarily responsible
for the transcription of MCP-1 and adhesion
molecules,12 13 leading to inflammation. NF-B also
regulates the transcription of tissue factor (TF). TF initiates the
extrinsic coagulation through an enzymatic factor VII/factor VIIa
complex formation. Constitutive TF expression by mesenchymal cells in
the adventitial blood vessel lining normally precludes TF interaction
with factor VII in plasma but allows activation of coagulation when the
endothelium is damaged.14 TF plays an
important role in cardiovascular diseases but also has
biological functions independent of the clotting
cascade.15 16 17 18 19 Rats harboring both human renin and
angiotensinogen genes (dTGR) develop hypertension and
severe renal and cardiac damage.20 21 NF-B activation,
MCP-1 production, adhesion molecule expression, and
inflammation are prominent features in the damaged kidneys of
dTGR.21 22 We provide evidence that bosentan inhibits Ang
II–induced NF-B and AP-1 activation, prevents inflammation, and
ameliorates end-organ damage. We show that ETA/B
receptor blockade decreases TF expression in Ang II–induced
vasculopathy, which may ameliorate the microthrombosis featured in this
model. |
Methods |
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Four-week-old male age-matched and body weight–matched dTGR and Sprague Dawley (SD) rats were used as described elsewhere.20 All procedures were done according to guidelines from the American Physiological Society. We compared untreated dTGR (n=20), bosentan-treated (100 mg/kg for 3 weeks by gavage once a day; n=15), hydralazine-treated dTGR (80 mg/L in the drinking water for 3 weeks; n=15), and SD control rats (n=10) receiving vehicle (1% sodium carboxymethylcellulose). This bosentan dosage produces a maximal pharmacological effect in rats.23 Systolic blood pressure was measured at weeks 6 and 7 by the tail-cuff method under light ether anesthesia 20 hours after the last drug dose. Urine was collected over a 24-hour period. Rats were killed at age 7 weeks. The kidneys and hearts were washed with ice cold saline, blotted dry, and weighed. For Western blot and NF-
B analysis, the tissues
were snap-frozen in liquid nitrogen, for immunohistochemistry in
isopentane (-35°C), and stored at -80°C.
Tissue preparation and immunohistological techniques
were performed as described before in detail.24 The
sections were incubated with primary monoclonal antibodies against rat
monocytes/macrophages (ED-1, Serotec), NF-B subunit p65
(Roche Boehringer), ICAM-1 (1A29, R&D Systems), LFA-1 (WT.1,
Pharmingen), VLA-4 (TA-4, Pharmingen), and with polyclonal antibodies
against TF (gift of Dr Th. Luther, TU Dresden, Germany), PAI-1
(American Diagnostica), and fibronectin (Paesel-Lorei).
Scoring of ED-1–, LFA-1–, and VLA-4–positive cells was performed
with the use of the program KS 300 3.0 (Zeiss). Fifteen different areas
of each heart and kidney (n=4 to 5 in all groups) were analyzed
without knowledge of rat identity. Urinary ET-1 concentration was
determined by radioimmunoassay as described previously.25
Quantitative determination of albumin concentration in the
urine was performed with the use of a commercially available rat
albumin ELISA kit (Celltrend). Urinary ET-1 concentrations were
normalized to urinary creatinine concentrations.
Tissue preparation for electrophoretic mobility shift assay (EMSA) was
performed as described before in detail.24 Total tissue
homogenates were incubated in a binding reaction medium
with 0.5 ng of 32P-dATP end-labeled
oligonucleotide, containing the NF-B binding site
from the MHC enhancer (H2K, 5'-gatcCAGGGCTGGGGATTCCCCATCTCCACAGG).
For AP-1, double-stranded oligonucleotides containing
the consensus sequence for AP-1 (Santa Cruz, 5'-GAT CGA ACT GAC CGC CCG
CCG CCC GT-3') were radiolabeled with 
-32P
with the use of T4 polynucleotide kinase by standard
methods and purified over a column. The DNA-protein complexes were
analyzed on a 5% polyacrylamide gel, 0.5% Tris
buffer, dried, and autoradiographed. In competition assays, 50 ng
unlabeled H2K or AP-1 oligonucleotides were used.
Homogenates (50 ng) were used for Western blot and stained
with polyclonal I-kB
antibody (FL).
Data are presented as mean±SEM. Statistically significant differences in mean values were tested by ANOVA, blood pressure by repeated ANOVA, and the Scheffé test. A value of P<0.05 was considered statistically significant. The data were analyzed with the use of Statview statistical software.
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Results |
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The renal tubules were swollen and filled with proteinaceous material in untreated dTGR. Renal and cardiac vessels showed increased intimal and medial thickness as well as microthrombi. Bosentan prevented vasculopathy and extracellular matrix formation. In contrast, hydralazine-treated sections appeared similar to untreated dTGR (data not shown). Nine (45%) of 20 untreated dTGR died at 7 weeks, whereas only 1 (7%) of 20 of the bosentan-treated and 4 (26%) of 15 hydralazine-treated rats died before the end of the study. Urinary ET-1 levels were significantly increased by 50% in untreated dTGR compared with SD rats, respectively (989±52 versus 646±50 pg ET-1/mg creatinine by week 7). Untreated dTGR, bosentan-treated dTGR, and hydralazine-treated dTGR were hypertensive at weeks 6 and 7 compared with SD (Figure 1A). Bosentan and hydralazine decreased blood pressure (Figure 1A) and cardiac weights (expressed as mg/g body wt) (Figure 1B). Body weight was not significantly different between the groups. Albuminuria (Figure 1C) was significantly reduced with bosentan but not with hydralazine.
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We next investigated transcription factor activation influencing
VCAM-1, ICAM-1, and TF gene expression. EMSA for
the detection of NF-B showed a greater DNA binding activity in the
kidneys of untreated dTGR compared with bosentan-treated or SD controls
(Figure 2A). On the other hand,
hydralazine-treated dTGR were not distinguishable from
untreated dTGR with respect to NF-B activity. Thus, bosentan
treatment reduced levels of NF-B in kidney and heart (heart data not
shown). Binding specificity was demonstrated by competition of excess
unlabeled oligonucleotides containing the B site
from the MHC enhancer (H2K) (Figure 2B). Semiquantification is
given in Figure 2C. Western blot analysis showed reduced
levels of I-B in untreated and hydralazine-treated dTGR
kidney (Figure 2D), whereas bosentan ameliorated I-B
reduction. Bosentan but not hydralazine also decreased AP-1 DNA
binding activity in heart (Figure 2E) and kidney (kidney data
not shown). Binding specificity (Figure 2F) and
semiquantification (Figure 2G) corroborated the results.
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Immunohistochemical analysis (phase-contrast resolution) shows
the localization of the subunit p65 of NF-B in the kidney (Figure 3). The expression of p65 was increased
in the endothelium (Figure 3A), smooth muscle
cells of small vessels (Figure 3A), glomeruli (Figure 3B), infiltrating cells (Figure 3, A through C), and
tubules (Figure 3C) of untreated dTGR. No immunoreaction was
observed in nontransgenic SD rats (Figure 3, D through F). The
NF-B activity in the kidney was markedly reduced by bosentan
compared with untreated or hydralazine-treated dTGR (Figure 4, A through D). We next investigated TF,
which also contains B and AP-1 binding sites in the promoter.
Untreated and hydralazine-treated dTGR showed an increased TF
expression (Figure 4, E through H), which resembles the
localization of p65 in the vessel wall. Bosentan markedly reduced TF
expression. VCAM-1 (Figure 5, A through
D) and ICAM-1 (Figure 5, E through H) expression in dTGR kidneys
and hearts (data not shown) was increased in the intima, whereas ICAM-1
was also increased in adventitia, glomeruli, tubules, and in the
peritubular space. ICAM-1 and VCAM-1 expression was reduced by
ETA/B receptor blockade but not by
hydralazine. However, bosentan was more effective in the kidney
than in the heart.
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Immunohistochemical analysis of the integrins VLA-4 and LFA-1 in the kidney of untreated and hydralazine-treated dTGR showed increased expression in the perivascular space and adventitia. The semiquantification of the counterreceptors for VCAM-1 and ICAM-1 (Figure 6) showed that bosentan reduced VLA-4 by 60% (Figure 6A) and LFA-1 by 70% (Figure 6B) in the kidney compared with untreated dTGR, respectively. There was significant perivascular monocyte/macrophage infiltration in the kidney and heart of untreated dTGR. Cell count analysis (Figure 6C) showed a significant reduction in the mononuclear cell infiltration after bosentan treatment in kidney and heart compared with the hydralazine-treated and untreated dTGR (heart data not shown). The monocyte recruitment in the vascular wall was accompanied by increased PAI-1 expression (data not shown) in the same areas and accumulation of extracellular matrix protein. Fibronectin (Figure 7, A through D) was completely reduced in the kidney and moderately reduced in the heart by bosentan treatment compared with untreated and hydralazine-treated dTGR (Figure 7, E through H).
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Discussion |
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We tested the hypothesis that bosentan treatment inhibits NF-
B
activation, prevents inflammatory responses, and ameliorates Ang
II–induced cardiac and renal damage. Furthermore, we investigated the
effect of bosentan on TF, which is the major initiator of the
coagulation pathway in vivo.17 Our animal model features
hypertension, vasculopathy, severe renal damage, cardiac
hypertrophy, inflammation, focal necrosis in heart and
kidney, and a 45% mortality rate at 7 weeks.20 21 We
found that bosentan but not hydralazine ameliorated end-organ
damage. Both drugs decreased blood pressure and cardiac
hypertrophy slightly; however, albuminuria was
only reduced after ETA/B receptor blockade. We
recently showed that Ang II–independent treatment with
hydralazine, reserpine, and hydrochlorothiazide
to normotensive levels merely delayed organ damage and inflammation in
dTGR.26 That study demonstrated that Ang II–independent
normalization of blood pressure reduced cardiac hypertrophy
to a minor extent. In contrast, a human specific renin
inhibitor, which was only partially active on blood
pressure, led to a significant reduction in cardiac
hypertrophy, compared with triple therapy.26
By using Tsukuba mice overexpressing the human renin and
angiotensinogen genes, Kai et al23 showed that
a blood pressure reduction with hydralazine did not prevent
cardiac hypertrophy and nephropathy. In the present study, hydralazine treatment resulted in a slight but significant reduction in cardiac hypertrophy. However, hydralazine did not decrease AP-1 DNA binding activity and extracellular matrix formation in heart and kidney. We speculate that the reduction in cardiac hypertrophy by hydralazine may be overestimated because 26% of hydralazine-treated rats died before the end of the study. Autopsies of all hydralazine rats, which were not included in the cardiac hypertrophy index, showed enlarged hearts. In addition, Ang II is known to stimulate immediate early genes, cell proliferation, and hypertrophic responses.27 28 29
Recently, 2 groups showed that Ang II induced c-fos,
c-jun, and AP-1 activity in vascular smooth muscle
cells.27 28 Bosentan was able the reduce AP-1 DNA
binding activity and AP-1 regulated fibronectin formation in the heart.
Thus, reduction of cardiac hypertrophy by bosentan may be
partially mediated by AP-1. In contrast, bosentan reduced blood
pressure only to 
165 mm Hg. Therefore, mechanical load may
have counterregulated the reduction of hypertrophy.
Altogether, treatment with bosentan also ameliorated cardiac
vasculopathy and fibrosis as well as inflammation.
Ang II is a powerful stimulator of ET-1 in vascular smooth muscle and endothelial cells.5 6 7 Tissue ET-1 induced by Ang II is known to induce vascular hypertrophy.9 10 However, reports on the effectiveness of ET-1 receptor blockers in Ang II–induced end-organ damage are conflicting.30 31 32 Herizi et al31 showed that bosentan ameliorated end-organ damage in Ang II–infused rats. We were thus not surprised to find that bosentan ameliorated the severity of vascular damage in dTGR. Recently, Randolph et al30 showed reduced left ventricular hypertrophy as well as ß-myosin heavy chain and ANP gene expression in the early phase of renovascular hypertension after ETA receptor blockade, independent of blood pressure. In contrast, Li et al32 were not able to show beneficial effects of bosentan in 2-kidney 1-clip renovascular hypertensive rats. However, Li et al32 used rats that had already developed hypertension and presumably already had end-organ damage. Thus, they studied disease regression. In addition, the late phase of 2-kidney 1-clip hypertension may be less dependent on high Ang II levels.
We sought to elucidate molecular mechanisms involved in the
pathogenesis of end-organ damage in dTGR and the possible role of
endothelin as a mediator. Several reports have demonstrated the
participation of macrophages in the onset and progression of
various kidney diseases.33 34 Cell surface adhesion
molecules could play a major role in mediating cell recruitment.
NF-B, the main factor in the transcription of VCAM-1 and ICAM-1,
plays an important role in various cardiovascular
diseases. Several studies have shown that NF-B plays an important
role in cardiac and renal end-organ damage. Zhang et al35
have shown that ACE inhibition decreased NF-B in kidneys with
ureteral obstruction. Ruiz-Ortega et al13 have reported
that NF-B and MCP-1 activation in the renal cortex was reduced by
ACE inhibition in experimental immune complex nephritis. They also
showed that Ang II stimulated NF-B and MCP-1 in
mesangial cells. Morishita et al36 showed that
NF-B inhibition by a decoy technique reduced the extent of
myocardial infarction after reperfusion. End-organ damage in dTGR was
accompanied by the activation of NF-B and AP-1 in both the kidney
and heart. However, Ang II–induced inflammatory response,
vasculopathy, and the induction of the various NF- B– and/or
AP-1–regulated genes was more prominent in the kidney compared with
the heart. Bosentan ameliorated renal and cardiac damage; however,
renal protection was more efficient. Recently, we showed that the
unselective NF-B inhibitor PDTC reduced
albuminuria by >90%.24 However, PDTC reduced
blood pressure, inflammation, cardiac vasculopathy, and cardiac
hypertrophy similar to bosentan. Thus, NF-B plays a role
in both cardiac and renal damage. Remuzzi and Bertani37
have shown that filtered albumin is able to activate
NF-B. They demonstrated that increased glomerular
permeability is followed by increased filtration of macromolecules,
followed by excessive tubular protein reabsorption.37 38
This process leads to abnormal accumulation of proteins in
endolysosomes and endoplasmic reticulum. Altogether, these
processes foster the activation of NF-B–dependent and
NF-B–independent cytokines, resulting in renal
inflammation. Inhibition of NF-B by bosentan treatment may have
inhibited both the direct activation of NF-B by Ang II as well as
the subsequent activation induced by the increased
glomerular permeability in our model, thereby breaking the
self-amplifying loop. Thus, NF-B inhibition may be an additional
mechanism that might further explain the anti-inflammatory effects of
ET-1 receptor blockers in progressive kidney disease.
TF plays an important role in vasculopathies, reperfusion injury, preeclampsia, and kidney disease.15 16 17 18 39 Ang II stimulates TF.15 40 TF expression in dTGR was predominantly located in the walls of damaged vessels, which also stained positive for p65. Integrin-matrix signaling is also known to play an important role in inflammation and coagulation41 The Ang II–induced formation of fibronectin in the kidney and heart was reduced by bosentan treatment, an effect that could have mechanistic implications. Several reports suggest that the ß1 integrin VLA-4 induces monocyte procoagulant activity.42 43 McGilvray et al42 showed that the VLA-4 integrin cross-linked on human monocytes induces TF expression by a mechanism involving mitogen-activated protein kinase. We found marked infiltration of VLA-4–positive cells in dTGR kidneys, which was reduced after ETA/B receptor blockade. Thus, it is tempting to speculate that VLA-4/fibronectin signaling also stimulates TF expression in our model. Recently, Giesen et al18 and Nemerson and Giesen19 showed that in addition to the scheme whereby coagulation is initiated after vessel damage and blood exposure to vessel wall–bound TF, leukocytes are the main source of blood-borne TF. dTGR showed both vessel wall damage and leukocyte activation, which may both have influenced TF activity.
In summary, we showed that bosentan decreased blood pressure and
cardiac hypertrophy and provided considerable renal
protection in Ang II–induced end-organ damage. Vascular injury was
largely prevented, and mortality rate was reduced. The amelioration of
renal damage was provided by ETA/B receptor
blockade, since hydralazine treatment was not effective. We
provide evidence that long-term ETA/B receptor
blockade in vivo inhibits renal NF-B activation and TF expression in
Ang II–induced vasculopathy. Bosentan also markedly reduces the
expression of NF-B–regulated genes such as VCAM-1 and
ICAM-1 and thereby diminishes monocyte infiltration. These
findings suggest that ETA/B receptor blockade may
provide an anti-inflammatory and antithrombotic effect that could
extend to other kidney diseases.
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Acknowledgments |
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This study was supported by a grant-in-aid from Hoffmann-La Roche, Basel, Switzerland. Eero M.A. Mervaala was supported by the Alexander von Humboldt Foundation, the Finnish Foundation for Cardiovascular Research, and the Academy of Finland. Dominik N. Muller was supported by the Klinisch Pharamakologische Verbund Berlin-Brandenburg. Karin Dressler, Mathilde Schmidt, and Christel Lipka gave expert technical assistance. Dominik N. Muller and Eero M.A. Mervaala contributed equally.
Received February 14, 2000; first decision February 23, 2000; accepted March 3, 2000.
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