(Hypertension. 2000;36:330.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Angiotensin II Activates Collagen I Gene Through a Mechanism Involving the MAP/ER Kinase Pathway
From INSERM U.489, Hôpital Tenon, Paris, France (P.-L.T., C.C., F.F.), and AP-HP, Laboratoire de Physiologie, UFR St Antoine, Paris (J.-C.D.).
Correspondence to Jean-Claude Dussaule, MD, AP-HP, Laboratoire de Physiologie, UFR St Antoine, Paris 75012, France. E-mail jean-claude.dussaule{at}sat.ap-hop-paris.fr
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Abstract |
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Abstract—Vascular remodeling and rearrangement of the extracellular matrix formation are among the major adaptive mechanisms to chronic increase in blood pressure. In previous studies we have found that angiotensin II (Ang II) participates in the hypertension-associated aortic and renal vascular fibrosis by stimulating collagen type I formation. The purpose of the present study was to gain insight into the molecular events that lead from the Ang II receptor to collagen I gene activation. To this end, we used a novel strain of transgenic mice harboring the luciferase gene under the control of the collagen I-
2 chain
promoter [procol2(I)]. Ang II produced an early (1
hour) 2- to 3-fold stimulation of procol2(I) activity in
freshly isolated aortas and renal cortical slices
(P<0.01) followed by similar increase in
procol2(I) mRNA aortic levels. This effect of Ang II was
inhibited by AT1-receptor antagonism (candesartan) and blockade of the
MAPK/ERK cascade (PD98059); in contrast, inhibition of the P38 kinase
pathway (SB202190) and blockade of the release of the transcription
factor NF
B (PDTC) did not have any effect in the Ang II–induced
activation of the collagen I gene. In addition, Ang II induced a rapid
(5 minutes) increase of the MAPK/ERK activity that was accompanied by
increased expression (3-fold) of the c-fos
proto-oncogene. This increase of c-fos mRNA expression
was blocked by PD98059; in addition, curcumin, a blocker of the
transcriptional factor AP-1, canceled the effect of Ang II on the
collagen I gene. Decorin, a scavenger of the active form of
transforming growth factor-ß (TGF-ß), canceled the Ang II effect on
collagen I gene, whereas inhibition of the MAPK/ERK pathway had no
effect on the TGF-ß–induced activation of procol2(I).
These data indicate that the cellular events after AT1 receptor
stimulation and leading to activation of collagen I gene expression
require activation of both the MAPK/ERK and TGF-ß signaling
pathways.
Key Words: collagen • angiotensin II • fibrosis • kinase • extracellular matrix • transforming growth factors
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Introduction |
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Hypertension is usually associated with the development of vascular and renal fibrosis.1 This pathophysiological process is characterized by structural changes in vasculature caused by increased synthesis and rearrangement of extracellular matrix proteins, such as the collagen type I.2 Several studies support a major role for the renin-angiotensin system in the development of fibrosis.3 4 Although the cellular mechanism(s) of the angiotensin II (Ang II)-induced vasoconstriction have been extensively studied, it remains less known what is (are) the signaling pathway(s) involved in the fibrogenic action of Ang II.
In previous studies, we investigated the role of Ang II in the
mechanisms of renal vascular fibrosis during hypertension by using a
new strain of transgenic mice.5 These mice express the
luciferase reporter gene under the control of the promoter of the
2 chain of collagen I gene
[procol2(I)].6 We have
established that luciferase and collagen I gene expressions are closely
correlated from the fetal development throughout the adult life under
normal or pathophysiological conditions either in
vivo or in freshly isolated tissues ex vivo.5 6 7 In
particular, we investigated whether Ang II played a role in the
mechanism(s) controlling the development of renal vascular and aortic
fibrosis during hypertension. To this end, hypertension was induced in
the procol2(I) transgenic mouse by inhibiting
nitric oxide synthesis, and the activation of collagen I gene was
estimated in several vascular tissues such as afferent arterioles,
glomeruli, heart, and aorta. We observed that pharmacological blockade
of angiotensin receptors (AT1) completely suppressed the
activation of collagen I gene and protected animals from the
development of vascular fibrosis.5
The objective of the present study was to get insight into the
cellular events after Ang II binding to its receptors and leading to
collagen I gene activation. To this end, we tested in freshly isolated
aortas and renal cortical slices the involvement of 3 pathways,
MAPK/ERK, NFB, and P38, thought to be among the major mediators of
the mitogenic action of Ang II that use specific
inhibitors or blockers of their enzymatic cascades. In
addition, we investigated how transforming growth factor-ß (TGF-ß),
another potent fibrogenic agent, participates in the Ang II–induced
stimulation of procol2(I). Our data indicated
that the MAPK/ERK cascade is an important mediator in the signaling
pathway leading from Ang II to collagen I gene activation. Moreover, we
observed that although biological activity of TGF-ß is required for
collagen I gene activation, this action of TGF-ß is insensitive to
MEK blockade, the upstream kinase of MAPK/ERKs.
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Methods |
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Animal Treatment
Male transgenic mice weighing 25 to 35 g (3 to 6 months old) at the time of the experiments were maintained on a normal salt diet. Animals had free access to chow and tap water. This transgenic line, named pGB 19.5/13.5, was generated in the laboratory of B. de Crombrugghe (University of Texas, Houston).6 These animals harbor a construction containing the sequences -19.5 to -13.5 kb and -350 to +54 bp of the promoter of the
2 chain
of mouse collagen type I gene linked to 2 reporter genes, the firefly
luciferase and the Escherichia coli ß-galactosidase. The
choice of these mice was based on previous studies showing that the
expression pattern of the two reporter genes in embryos and adult
animals closely correlates with cell and tissue distribution of
collagen I.5 6 7 The protocol followed the INSERM
guidelines for animal care and protection.
Ex Vivo Addition of Ang II or TGF-ß
Experiments were performed on freshly isolated renal cortical
slices and aortas incubated in RPMI 1640 medium (containing 10
mmol HEPES, 2 mmol/L L-glutamine, 100 U/mL penicillin,
and 100 mg/L streptomycin) for up to 1 hour at room temperature. Ang II
(100 nmol/L) was added either alone or in combination in tissues
preincubated for 5 minutes with candesartan (100 nmol/L, AT1-receptor
antagonist), PD 98059 (50 µmol/L, specific
inhibitor of MEK), SB 202190 (30 µmol/L, P38 kinase
inhibitor), curcumin (20 µmol/L, AP-1 blocker),
pyrrolidinedithiocarbamate (PDTC 100 µmol/L, NFB
inhibitor), or decorin (100 nmol/L, TGF-ß scavenger). In
separate experiments, TGF-ß1 (0.8 nmol/L) was
added with or without PD98059, curcumin, or decorin. In each
experiment, segments of aorta or renal cortical slices from the same
animal were used in a paired fashion to compare the effect of Ang II or
TGF-ß1 without versus with the different
inhibitors. After 1 hour of incubation, tissues were lysed,
and luciferase or MAP kinase activity was measured as described
below.
Assays for Expression of Luciferase
Luciferase activity was measured with a commercial reporter gene
assay kit (Boehringer Mannheim) in homogenized
tissues with the aid of a Lumat LB 9507 luminometer (EG & Berthold) as
previously described.5 7 Results are expressed as
luciferase light units per microgram of protein (LU/µg).
Measurement of MAPK Activity
MAP kinase activity was assayed with the p42/p44 MAP kinase
enzyme assay system (Amersham), as described elsewhere.8
The enzymatic reaction was performed at 30°C for 30 minutes. ERK
activity was normalized to the protein content of supernatants.
Estimation of c-fos and 2 Collagen I
mRNA by Reverse Transcription–Polymerase Chain Reaction
One microgram of RNA extracted from aortas by use of the Trizol
kit (Life Technologies LTD) was reverse-transcribed by means of the
Superscript II protocol (Life Technologies LTD). One microliter of the
reverse transcription (RT) reaction was incorporated in the polymerase
chain reaction (PCR) (buffer: 2 mmol/L
MgCl2, c-fos primers 15 pmol each,
GAPDH primers 0.2 pmol each, 0.2 mmol/L dNTP, 1 U Taq DNA
polymerase) and initially denatured for 5 minutes at 94°C.
We used oligonucleotides specific for c-fos (Stratagene): sense: GCT TTC CCC AAA CTT CGA CCA TG; antisense: CTG TCA CCG TGG GGA TAA AGT TGG; and oligonucleotides specific for GAPDH (Genset): sense: ACC ACA GTC CAT GCC ATC AC; antisense: TCC ACC ACC CTG TTG CTG TA.
The compatibility of primer pairs was verified with the use of Oligo4 software (Molecular Biology Insights). PCR products were sequenced (Genome Express) and compared with GenBank and EMBL genomic data bank with the BLAST algorithm to verify their identity with the theoretical targets.
The 28-cycle program performed with a Biometra-Trio-thermoblock thermocycler (Kontron Instruments) consisted of 45 seconds of denaturation at 94°C, 30 seconds of annealing at 60°C, and 1-minute extension at 72°C. After completion of the cycling program, samples were subjected to a 10-minute extension period at 72°C. Ten microliters of each PCR assay were run in a 2% agarose gel stained with ethidium bromide. After electrophoresis, gels were UV-transilluminated and digitalized. The optical densities of the bands corresponding to the coamplified c-fos (216-bp fragment) and GAPDH fragments (452-bp fragment) were calculated and compared by means of the NIH Image 1.61 software.
RT-PCR for the 2 chain of collagen I was
performed with the same methodology as described above, except the
number of cycles was 30. The primers used were previously
reported.9
Statistical Methods
Statistical analyses were performed with the paired
t test or ANOVA followed by protected least significance
difference Fisher’s test of the Statview software package. Results
with values of P<0.05 were considered statistically
significant. All values are mean±SEM.
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Results |
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Transgenic Model
The choice of these mice was based on previous studies showing that the expression pattern of luciferase in embryos and adult animals closely correlates with cell and tissue distribution of collagen I.6 7 For instance, tissues rich in collagen I (tail, skin) showed very high levels of luciferase activity (21 954±1183 and 8245±815 LU/mg for these tissues, respectively); tissues poor in collagen I (renal cortex, interlobular arteries, and afferent arterioles) showed little activity (184±23 and 214±25 LU/mg, for these tissues, respectively); and where collagen I is almost absent (glomeruli), there was negligible luciferase activity (19±2 LU/mg).7 In these previous studies, we have also observed that the changes of luciferase activity in the renal cortex reflect mainly the changes of the luciferase activity of the renal cortical vascular tissue (interlobular arteries, afferent arterioles, glomeruli).
Ang II–Induced Activation of Procol2(I)
Gene
First, we examined whether Ang II can induce collagen type I gene
activation in freshly isolated aortas and renal cortical slices in
vitro. As shown in Figure 1, Ang II
produced a 2-fold increase in luciferase activity in aortas (1936±217
versus 3815±402 LU/µg, P<0.01, in control and 1 hour
after Ang II, respectively, Figure 1, top). A similar
stimulatory effect was observed in renal cortical slices (178±17
versus 405±42 LU/µg, P<0.01, in control and 1 hour after
Ang II, respectively). This effect on
procol2(I) promoter was mediated through an
AT1 receptor activation, since it was completely canceled by
candesartan (2127±224, Figure 1, and 207±23 LU/µg, for aorta
and renal cortex, respectively).
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Effect of MAPK/ERK, NFB, or P38 Kinase Pathway Inhibition on Ang
II–Induced Procol2(I) Gene Activation
As shown in Figure 1, bottom, PD98059, a specific
MAPK/ERK-pathway inhibitor, blocked the stimulatory effect
of Ang II on procol2(I) gene in aorta
(3760±267 versus 1812±213 LU/µg, P<0.01, in Ang II and
Ang II+PD98059, respectively) and renal cortex (301±27 and 191±17
LU/µg, P<0.01). In contrast, addition of PDTC (NFB
inhibitor) or SB202190 (P38 inhibitor) did not
alter the Ang II–induced increase of luciferase activity (PDTC:
3421±324 and 328±39, SB202190: 3506±371 and 292±34 LU/µg, for
aorta and cortex, respectively).
Effect of MAPK/ERK Pathway Inhibition on Ang II–Induced
Procol2(I) mRNA Expression
To verify whether the above-mentioned changes of the
procol2(I) promoter were associated with
changes of procol2(I) mRNA expression, we
estimated by RT-PCR the ratio of optical density of collagen I
product over GAPDH product under control conditions and after
administration of Ang II in the presence or absence of the MEK
inhibitor PD98059. As shown in Figure 2, top, Ang II induced a 2-fold increase
of procol2(I) mRNA expression in aorta
(1.67±0.05 versus 0.85±0.03 ratio of optical density of
2 col I RT-PCR product on GAPDH
product, P<0.001, in Ang II and control, respectively).
As was the case with the procol2(I) promoter
activation, PD98059 blunted the stimulatory effect of Ang II on
procol2(I) mRNA expression (1.09±0.05,
P<0.01 versus Ang II alone, Figure 2).
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Ang II–Induced Activation of MAPK/ERK Activity
To verify whether Ang II could activate the MAPK/ERK
cascade, measurements of MAPK/ERK activity were performed in aortas of
the transgenic mice. In agreement with the literature,8
Ang II produced an early increase (150% increase at 5 minutes) of MAP
kinase activity that plateaued after 30 minutes (340% of baseline,
Figure 2, bottom). The Ang II–induced increase of MAPK/ERK
activity was completely inhibited by the AT1-receptor
antagonist candesartan (103% of baseline).
Effect of AP-1 Inhibition on Ang II–Induced
Procol2(I) Gene Activation
Ang II produced an early increase (peak at 15 minutes) of
c-fos mRNA expression in aortas of transgenic mice (Figure 3A). Concomitant addition of PD98059
canceled the Ang II–induced increase of c-fos mRNA
expression, suggesting involvement of MAPK/ERK in the Ang II–induced
c-fos synthesis. To investigate if the AP-1 transcriptional
complex was implied in the activation of the
procol2(I), experiments were performed in
which luciferase activity was measured in the presence and absence of
curcumin.10 As shown in Figure 3B, curcumin
completely canceled the Ang II–induced increase of luciferase activity
in aortas of transgenic mice. Similar results were obtained with renal
cortical slices (315±27 versus 153±13 LU/µg, P<0.03,
for Ang II and Ang II+curcumin, respectively).
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TGF-ß–Induced Procol2(I) Gene Activation
In these experiments, we tested whether TGF-ß interacted with
Ang II to activate the collagen I gene. Exogenous
TGF-ß1 increased 2-fold the luciferase activity
in aortas (1786±203 versus 2689±384 LU/µg, P<0.05, for
control and TGF-ß1, respectively, Figure 4, top). This increase was completely
blocked by decorin, a TGF-ß scavenger (1656±183,
P<0.05), but not by PD98509 or curcumin (2935±648 and
2612±384 LU/µg, for these 2 agents, respectively, Figure 4).
Interestingly, decorin inhibited the Ang II–induced increase of
luciferase activity (2923±315 versus 1945±224 LU/µg,
P<0.05, for Ang II and Ang II+decorin, respectively, Figure 4, bottom).
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Discussion |
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In the present study, a strain of transgenic mice harboring the luciferase reporter gene under the control of the collagen I promoter permitted us to investigate mechanism(s) that control the activation of collagen type I gene in aorta and renal cortex. Specifically, we found that Ang II can rapidly activate the procol
2(I) gene in freshly isolated aortic and
renal cortical tissues. Using specific inhibitors of
several intracellular signaling pathways, we observed that MAPK/ERK and
AP-1 played a major role in the Ang II–mediated activation of collagen
I gene. In addition, we confirmed the involvement of TGF-ß in this
action of Ang II. Interestingly, the mechanism by which TGF-ß induced
collagen I gene activation was insensitive to blockade of the
MAPK/ERK-AP-1 pathway.
Several recent studies point to a leading role of the
renin-angiotensin system in the development of renal and
cardiac fibrosis. For instance, Ang II stimulated collagen protein
synthesis in cultured cardiac fibroblasts in vitro and increased
collagen I mRNA expression in rat hearts in vivo.11 12 In
the L-NAME model of hypertension, we observed that AT1 antagonism
prevented activation of collagen I gene in the renal and aortic
vasculature and reduced the development of renal vascular
fibrosis.5 Similarly, ACE inhibition markedly reduced the
development of renal and cardiac fibrosis and improved survival of rats
during chronic inhibition of nitric oxide.13 Our
present data clearly indicate that Ang II produced an AT1
receptor–mediated increase of collagen I gene expression in freshly
isolated renal and aortic vascular tissues. The magnitude of the
procol2(I) increase (2- to 3-fold versus
baseline) and the kinetics were similar to those previously observed
when Ang II was administered in the same strain of mice in
vivo.5 Evaluation of mRNA expression of the
2 chain of collagen I by RT-PCR confirmed the
Ang II–induced activation of the collagen I gene, at least up to the
mRNA level (Figure 2).
It is well established that the mitogenic action of Ang II
in the vascular smooth muscle cells is mediated mainly by the MAPK/ERK
enzymatic cascade. It is also known that exogenous administration of
Ang II is usually accompanied by increased MAPK/ERK activity in
vascular tissues. For instance, acute in vivo or ex vivo administration
of Ang II produced a marked increase of ERK activity in rat
aortas.8 14 In addition, the glomerular ERK
activity was 2- to 3-fold increased during prolonged infusion of Ang
II.15 In contrast, it is less clear what the contribution
of this pathway is in the vascular fibrosis induced by Ang II. Our
results show that Ang II increased procol2(I)
expression through the AT1 receptor (Figure 1) and that this
increase was accompanied by a rapid stimulation of MAPK/ERK activity
(Figure 2). These two phenomena were associated because specific
inhibition of MEK completely blocked the Ang II effect on collagen I
gene activation evaluated by luciferase activity and RT-PCR. To our
knowledge, this is the first study that establishes a link between Ang
II, AT1 receptor, MAPK/ERK activity, and
procol2(I) activation in freshly isolated
vascular and renal tissues.
Ang II can also induce oxidative stress-dependent effects in vascular
smooth muscle cells, leading to hypertrophy and
proliferation.16 These events are usually associated with
rapid release of NFB and/or P38 MAPK activation in
vitro.17 However, the activation of these two pathways by
Ang II may not be directly linked with fibrogenesis. In this regard,
chronic administration of an ACE inhibitor reduced the
arterial expression of NFB and of proinflammatory
chemokines without impeding the increased levels of mRNA expression and
protein content of collagen I in a model of
atherosclerosis in rabbits.18 In our
experiments, neither the NFB nor the P38 inhibitor
altered the increased procol2(I) expression in
aorta and renal cortex. Thus, contrary to MAPK/ERK cascade, these
redox-sensitive signaling pathways play a negligible role in the acute,
Ang II–induced activation of collagen I gene.
A major downstream signal after MAPK/ERK activation is the
phosphorylation of Elk-1/TCF transcription
factors, leading to the induction of c-fos proto-oncogene
expression to form the AP-1 transcriptional
complex.19 The AP-1 complex is usually an heterodimer
formed by c-Fos and c-Jun. Contrary to the
c-Fos expression that is inducible, c-Jun can be
present constitutively or activated through the
Jun kinase pathway. Our data showing that Ang II increased
c-fos mRNA expression and that this increase was blocked in
the presence of an MEK inhibitor (Figure 3) suggest
that c-fos is involved in the fibrotic effect of Ang II. It
is also possible that Ang II activated the Jun
kinase pathway. In this regard, Ang II stimulated PDGF mRNA expression
and induced cell proliferation in vascular smooth muscle cells in vitro
by activating both ERK and JNK pathways.20 The use of
curcumin does not allow us to exclude the concomitant activation of
both pathways because it prevents the c-Fos/c-Jun
complex from binding to the AP-1 motif of DNA.10
Whatever the case is, the promoter of the 2
chain of collagen I contains several sites of AP-1
recognition,21 22 thus supporting our hypothesis of an Ang
II–MAPK/ERK–AP-1 interaction.
Activation of the MAPK/ERK–AP-1 signaling pathway has been proposed to mediate the suppressor, antifibrotic action of estradiol in cultured mesangial cells.23 However, this hypothesis contrasts with the findings of another study in which the antimitogenic, antifibrotic effects of estrogens were attributed to the inhibition of the MAPK/ERK cascade activity in human aortic smooth muscle cells.24 Moreover, estrogens reversed the Ang II–induced increase of MAPK activity in human vascular smooth muscle and endothelial cells.25
TGF-ß is another known activator of collagen I gene
expression, and several studies associate the fibrogenic action of Ang
II to TGF-ß.26 In addition, the TGF-ß promoter
contains AP-1–dependent transcriptional regulatory
domains.27 For these reasons, we tested next whether
TGF-ß could be involved in the Ang II–MAPK/ERK–
procol2(I) interaction by using decorin, a
scavenger of its active form. Interestingly, neither MAPK/ERK
inhibition nor AP-1 blockade altered the TGF-ß–induced stimulation
of procol2(I) activity (Figure 4),
whereas decorin effectively canceled the Ang II–induced collagen I
gene activation. This finding leads us to propose the following
alternatives: one hypothesis is that Ang II increased
procol2(I) expression by a
MAPK/ERK–AP-1–dependent induction of TGF-ß activation, as was the
case in mesangial or aortic smooth muscle
cells.28 29 30 Another alternative is that Ang II
activated in parallel 2 signaling pathways, MAPK/ERK–AP-1 and
TGF-ß–Smads and that both cooperate and are necessary to induce
procol2(I) expression. In this regard, it was
recently reported that MAPK/ERK and TGF-ß–Smad signaling pathways
may converge at the AP-1 binding promoter sites.31 32 A
third mechanism, proposed for fibronectin production in human
vascular smooth muscle cells, is that TGF-ß contributed in part to
the PKC-induced increase of MAPK activity, which in turn
activated the collagen I gene.33 It has been also
observed that addition of TGF-ß in human mesangial cells
in vitro induced ERK phosphorylation and activation of
the promoter of collagen I.34 This activation of collagen
I promoter was inhibited by PD98059 but not by Jun kinase
blockade. In our experimental setting, the ERK inhibitor
had no effect on the TGF-ß–induced activation of the collagen I
promoter. This can be due to a species difference (although the
collagen I gene is extremely preserved within different species) or
tissue/cell-type difference (freshly isolated aortas versus cultured
mesangial cells). It has been also proposed that the
MAPK/ERK pathway could act at a transcriptional level by activating
extracellular matrix protein genes (fibronectin), whereas TGF-ß could
act at a posttranscriptional level by stabilizing
mRNA.35 This kind of interaction seems unlikely to
our case, because TGF-ß increased the activity of collagen I promoter
(Figure 4).
In conclusion, we investigated mechanisms leading to the increased expression of collagen I gene in aortic and renal vascular tissues by using a new model of transgenic mouse harboring the luciferase reporter gene under the control of collagen I promoter. Our data indicate that the fibrogenic effects of Ang II are mediated through the AT1 receptor; furthermore, the cellular events after AT1 receptor stimulation and leading to activation of collagen I gene expression require TGF-ß and a MAPK/ERK-mediated formation of the AP-1 transcriptional complex. The mechanisms of the interaction between these two pathways will be pursued in future studies.
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Acknowledgments |
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This work was supported by the "Institut National de la Santé et de la Recherche Médicale" and the "Faculté de Médecine St Antoine." Dr Pierre-Louis Tharaux was an INSERM research fellow; Dr Fadi Fakhouri was research fellow of the "Fondation pour la Recherche Médicale." The authors thank Drs George Bou-Gharios, Jerôme Rossert, and Benoit de Crombrugghe (Department of Molecular Genetics, University of Texas, Houston) for providing the transgenic mice, Claude Kitou and Laetitia Breton for animal care, and Astra for providing candesartan.
Received February 14, 2000; first decision February 29, 2000; accepted April 11, 2000.
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