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*INSERM U.489, Hôpital Tenon, Paris, France; and AP-HP, Laboratoire de Physiologie, Faculté de Médecine St Antoine, Paris, France.
Correspondence to Dr. Christos Chatziantoniou, INSERM U.489, Hôpital Tenon, Paris 75020, France. Phone: 331-56-01-66-58; Fax: 331-43-64-54-48; E-mail: christos.chatziantoniou{at}tnn.ap-hop-paris.fr
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Abstract |
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2 chain promoter (procol2[I]). Bolus intravenous administration of AngII or ET produced a rapid, dose-dependent activation of collagen I gene in aorta and renal cortical slices (threefold increase over control at 2 h, P < 0.01). The AngII-induced effect on procol2(I) was completely inhibited by candesartan (AngII type 1 receptor antagonist) and substantially blunted by bosentan (dual ET receptor antagonist) (P < 0.01), whereas the ET-induced activation of collagen I gene was blocked only by bosentan. In subsequent experiments, TGF-ß (also administered intravenously) produced a rapid increase of procol2(I) in aorta and renal cortical slices (twofold increase over control at 1 h, P < 0.01) that was completely blocked by decorin (scavenger of the active form of TGF-ß). In addition, decorin attenuated the activation of collagen I gene produced by AngII (P < 0.01). These data indicate that AngII can activate collagen I gene in aorta and renal cortex in vivo by a mechanism(s) requiring participation and/or cooperation of ET and TGF-ß. |
Introduction |
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In previous studies, we investigated the role of AngII and ET-1 in the mechanisms of renal vascular fibrosis using a novel strain of transgenic mice that express the luciferase reporter gene under the control of the promoter of the 2 chain of the collagen I gene (procol2[I]) (10,11). In these mice, luciferase activity and collagen I gene expression are closely correlated from the fetal development stage throughout the adult life under normal and/or pathologic conditions (10–12); thus, this transgenic strain is a model well adapted for studying the mechanisms whereby collagen I gene is activated, such as renal vascular fibrosis. Using this transgenic model, we observed that the pharmacologic blockade of AngII or ET-1 blunted the development of nephroangiosclerosis in nitric oxide-deficient hypertensive rats, via an inhibition of collagen I gene activation. This protective effect of AngII and ET-1 antagonists was not associated with BP modifications, which suggests that the fibrogenic effect of AngII and ET-1 may be independent of their systemic hemodynamic effects. In addition, AngII and ET-1 increased procol2(I) activity in isolated renal cortical slices in vitro, and this effect of AngII appeared to be partly mediated by the action of ET-1 (11).
In this study, we studied the interactions among AngII, ET-1, TGF-ß, and collagen I gene activation in acute in vivo experiments performed in the same strain of transgenic mouse that we have used elsewhere (10,11). Specifically, we tested whether exogenous administration of AngII, ET-1, or TGF-ß activates collagen I gene in the aortic and renal cortical tissue and whether there is a cross-reaction of blockers of these systems that affect procol2(I) activation. The specific antagonists or blockers used were candesartan (an AngII type 1 [AT1] receptor antagonist), bosentan (a dual ET receptor antagonist), and decorin (a scavenger of TGF-ß). Decorin was administered during the 3 d preceding the experiment at the dose of 50 µg/d. According to the literature, this method of decorin administration is sufficient to inhibit the fibrogenic effect of a continuous infusion of TGF-ß (6). Evaluation of mRNA expression of the 1 and 2 chains of collagen I confirmed that these peptides induced activation of the collagen I gene, at least up to the mRNA level. Our observations suggest that AngII activates the collagen I gene through a mechanism that implies both ET-1 and TGF-ß.
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Materials and Methods |
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2 chain of mouse collagen type I gene linked to two reporter genes, firefly luciferase and Escherichia coli ß-galactosidase. The choice of these mice was based on previous studies that showed that the expression pattern of the two reporter genes in embryos and adult animals closely correlates with cell and tissue distribution of collagen I under normal and/or pathologic conditions (10–12).
Acute Administration of AngII, ET-1, and TGF-ß In Vivo
AngII, ET-1, and TGF-ß, alone or combined to their specific antagonists or blockers, were injected intravenously as boli of 100 µl in transgenic mice through the caudal vein. In a series of initial experiments, we tested a range of doses from 5 to 1000 ng for AngII and ET-1 and from 1 to 50 ng for TGF-ß. In the series of experiments with their antagonists, AngII and ET-1 were used at the dose of 200 ng and TGF-ß at the dose of 20 ng. Candesartan (AT1 receptor antagonist) and bosentan (dual ETA/B receptor antagonist) were used at doses from 100 to 2000 ng. In the Results section, we present the data obtained with the dose of 1000 ng for each, because this dose was the minimum required to completely inhibit the effect of AngII or ET-1, respectively, on luciferase activity. In preliminary experiments, candesartan, bosentan, or decorin administration did not change luciferase activity in renal and aortic tissues of control animals. In the series of experiments to establish the dose and time effect of AngII, ET-1, and TGF-ß, a total of 174 mice was used (6 mice/dose or time/agent). In the series of experiments to test the efficiency of inhibitors a total of 65 mice was used (5 mice x 6 doses for candesartan or bosentan, and 5 mice x 1 dose for decorin). In the series of experiments of cross-reaction a total of 120 mice was used (8 mice/condition). AngII, ET-1, TGF-ß1 and decorin were purchased from Sigma (St Louis, MO); candesartan and bosentan were kindly provided by Astra-Zeneca (Mölndal, Sweeden) and Actelion (Basel, Switzerland), respectively.
Tissue Isolation
Animals were anesthetized with pentobarbital at times varying from 30 min to 6 h after the intravenous bolus injections. After anesthesia, a midline abdominal incision was made, and the abdominal aorta was cannulated (Surflo 24G catheter, Terumo) below the renal arteries. The aorta above the kidney was ligated, the left renal vein was cut, and kidneys were perfused with ice-cold isotonic saline solution until all blood had been removed. All subsequent steps of isolation were performed at 4°C. The kidneys were removed, and decapsulated, and the cortex was dissected from the medulla. Ten to 15 mm of the thoracic aorta were also dissected from each animal. Thereafter, the isolated tissues were divided in two parts that were immediately frozen. One portion was used for measurement of luciferase activity and the other portion for RNA extraction.
Luciferase Activity Assay
Luciferase activity was measured by use of a commercial reporter gene assay kit (Boehringer Mannheim, Mannhein, Germany). Tissues were frozen immediately after removal, and 500 µl of lysis buffer that contained 0.1 M KH2PO4/K2HPO4 (pH 7.8) and 1 mM DL-dithiothreitol were added in each sample. Tissues were homogenized with a Polytron homogenizer, and cells were lyzed by use of three freezing-defreezing cycles. Thereafter, samples were centrifuged at 12,000 g for 15 min, and luciferase activity was measured in 50 µl of supernatant by use of a Lumat LB 9507 luminometer (EG & Berthold, Strasbourg, France). The protein content was estimated in pellets according to Bradford’s method. Results are expressed as luciferase light units per µg of protein (LU/µg).
Extraction and Estimation of mRNA for 1 and 2 Chains of Collagen I
The mRNA expression of collagen I1 and collagen I2 chains was evaluated by semiquantitative reverse transcription-PCR by use of GAPDH mRNA expression as a reference. One microgram of RNA was extracted from aorta or renal cortex by use of the Trizol (Life Technologies BRL, England) reagent and reverse-transcribed by use of the avian myeloblastosis virus reverse transcriptase protocol (Boehringer Mannheim). Primers for collagen I1 and collagen I2 chains were selected by the online Primer3 software (Massachusetts Institute of Technology, Cambridge, MA). The following primers were used: for the chain 1, sense 5'-ACGTCCTGGTGAAGTTGGTC-3' and antisense 5'-CAGGGAAGCCTCTTTCTCCT-3'; for the chain 2, sense 5'-TGTTCGTGGTTCTCAGGGTAG-3' and antisense 5'-TTGTCGTAGCAGGGTTC TTTC-3'; and for GAPDH sense, 5'-ACCACAGTCCATGCCATCAC-3' and antisense 5'-TCCACCACCC TGTTGCTGT-3'. The PCR product sizes were 169, 253, and 432 bp, respectively. A similar protocol was used for the evaluation of mRNA levels of TGF-ß, with the exception that the following primers were used: sense, 5'-AATACGTCAGACATTCGGGA-3' and antisense 5'-ACGTCAAAAGACAGCCACTC-3', with an expected product size of 193 bp. PCR products were sequenced (Genome Express) and compared with the basic alignment search tool algorithm (BLAST) to verify their identity with the theoretical targets. In preliminary experiments, samples were withdrawn at regular intervals between 26 and 34 cycles to verify the parallelism of the two slopes in the exponential phase of amplification. After electrophoresis, gels were digitalized and the densities of the corresponding bands were calculated by use of the NIH Image 1.61 software.
Measurement of BP
Systolic BP was measured as described elsewhere (10,11). Briefly, a piezoelectric sensor (Sensonor 840 to 01) connected to a carrier amplifier (Kent 2) was used to detect and convert heart pulses to electric signals. The outputs of the pressure transducer were interfaced to a data acquisition system composed of a Power PC Macintosh 4400/200 computer and a MacLab/4 s 16-bit analog-to-digital converter (ADInstruments) that allowed sampling at 40,000 samples/s. Pressure recording was analyzed by use of the Chart module of the Mac Lab software.
Statistical Analyses
Statistical analyses were performed by use of ANOVA followed by the protected least significance difference Fisher test of the Statview software package. Results with P < 0.05 were considered statistically significant. All values are means ± SEM.
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Results |
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2(I) in a dose-dependent manner in renal cortical slices and aortas (renal cortex, 166 ± 19 versus 108 ± 5 LU/µg; P < 0.05; and aorta, 2861 ± 717 versus 1569 ± 175 LU/µg; P < 0.05 for 50 ng of ET-1 and control, respectively). For both peptides, doses 
200 ng induced a two- to threefold increase of procol2(I) activity; for this reason, the dose of 200 ng for each peptide was used in subsequent experiments. The dose range for TGF-ß administration was slightly different; procol2(I) activity increased after 5 ng of TGF-ß (renal cortex, 160 ± 22 versus 120 ± 9 LU/µg; P < 0.05; aorta, 3480 ± 296 versus 2103 ± 238 LU/µg; P < 0.05 for 5 ng of TGF-ß and control, respectively) and reached a two- to threefold peak at the dose of 20 ng, which was used in subsequent experiments.
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2(I) activity that started after 30 min and reached a plateau after 2 to 4 h (Figure 1B). The time course of the increase of luciferase activity after injection of 200 ng of ET-1 was similar to that observed with AngII (renal cortex, 131 ± 7 versus 269 ± 14 LU/µg; P < 0.01; aorta, 1676 ± 106 versus 5026 ± 437 LU/µg; P < 0.01 for control and 2 h after ET-1, respectively), whereas the time course of TGF-ß action on procol2(I) activity was slightly shorter: luciferase activity peaked 1 h after injection of 20 ng of TGF-ß and started declining after 2 h (2277 ± 425 versus 3901 ± 410 and 2908 ± 217 LU/µg in aortas for control, 1 or 2 h after TGF-ß injection, respectively). On the basis of these results, tissues were isolated in subsequent experiments 2 h after AngII or ET-1 and 1 h after TGF-ß injections.
Next, we examined whether the peptide-induced activation of procol2(I) promoter resulted in increasing mRNA expression for both chains, 1 and 2, that form the mature molecule of collagen type I. As shown in Figure 2A, the same doses of AngII, ET-1, or TGF-ß that activated procol2(I) promoter were capable of increasing threefold mRNA expression of the 1 chain of collagen I in aortas. Similar results were obtained in renal cortical slices (+290, +280, and +250% over control, P < 0.01, for AngII, ET-1, and TGF-ß injections, respectively, Figure 2B). As with 1 chain mRNA expression, AngII, ET-1, or TGF-ß increased two- to threefold the mRNA expression of the 2 chain of collagen I (+270, +310, and +240% over control, P < 0.01, for the three peptides, respectively).
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2(I) Gene and on BP2(I) gene was completely inhibited by candesartan (P < 0.01), which indicates an AT1 receptor-mediated action of AngII. Interestingly, this pro-fibrogenic effect of AngII was also inhibited by bosentan, an ET-1 receptor antagonist, and decorin, a TGF-ß scavenger (P < 0.01, Figure 4). This inhibition appeared to be independent of systemic hemodynamics, because bosentan co-administration did not alter the AngII-induced transient increase of BP (Figure 3, right panel). Similarly, decorin did not change the systolic pressure response to AngII (Figure 3, right panel).
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2(I) Gene2(I) gene in the aortic tissue was blocked by the ETA/B receptor antagonist bosentan but not by candesartan or decorin (Figure 5, left panel). Similar data were obtained in renal cortical slices (Figure 5, right panel). The TGF-ß-induced increase of the procol2(I) gene in aortas was inhibited by its scavenger decorin but not by candesartan or bosentan (Figure 6, left panel). As shown in Figure 6, right panel, similar observations were made in renal cortical slices.
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2(I) gene, respectively, was due to its scavenging action on TGF-ß, measurements of mRNA levels of TGF-ß were performed after acute administration of AngII or ET-1 at the same doses that activated the procol2(I) gene. As shown on Figure 7, administration of AngII was followed by a transient increase of TGF-ß mRNA levels (+180% over control, P < 0.01, at 1 h). In contrast, 1 or 2 h after the ET-1 injections, expression of TGF-ß mRNA did not change compared with controls (Figure 7).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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2 chain-collagen I promoter permitted us to investigate fibrogenic mechanism(s) and to reveal a complex interaction between AngII, ET-1, and TGF-ß that controls the activation of collagen type I gene in the aortic and renal vascular tissues in vivo. Specifically, we found that exogenous administration of these peptides can activate the procol2(I) gene in a rapid and dose dependent manner. An important novel finding is that bosentan, an ETA/B receptor antagonist, and decorin, a TGF-ß scavenger, almost completely abolished the AngII-induced activation of procol2(I). This result suggests that ET-1 and TGF-ß are required and mediate (at least the acute) effect of AngII on the collagen I gene in the renal and vascular tissues. Several recent investigations have implied the renin-angiotensin and ET systems in the development of renal and vascular fibrosis through their action on extracellular matrix protein formation. Thus, AngII-stimulated collagen protein synthesis in cultured cardiac fibroblasts in vitro and increased collagen I mRNA expression in rat hearts in vivo (13–15). In the L-NAME model of hypertension, angiotensin-converting enzyme inhibition prevented the development of cardiac and renal fibrosis and improved survival (16–18). Similarly, antagonism of endothelin receptors inhibited extracellular matrix formation, improved renal structure damage, and delayed the progression of renal failure in the models of renal mass reduction or lupus nephritis (19–21). In some of these studies, there was dissociation between the hemodynamic and the fibrogenic actions of AngII and ET-1. Thus, angiotensin-converting enzyme inhibition, but not hydralazine, prevented vascular and myocardial remodelling in L-NAME-treated rats, despite the similarity of systolic BP levels in these two groups (16), whereas antagonism of the ETA receptor prevented proteinuria and glomerular ischemia and blunted the degree of vascular and tubulointerstitial injuries during inhibition of NO synthesis without normalizing BP (22).
In previous studies we investigated the involvement of AngII and ET-1 in the development of renal vascular fibrosis during chronic inhibition of NO synthesis (10,11,23). We found that the collagen I promoter was activated locally, in the renal resistance vessels and glomeruli, before the BP increase. Antagonism of AT1 or ETA/B receptors abolished the exaggerated collagen I gene expression and protected the renal vasculature from the development of fibrosis despite the persistent increase of systolic pressure in L-NAME-treated animals (10,11). The observation that both pharmacologic treatments inhibited collagen I gene activation to a similar degree and preserved equally the renal structure raises the question of whether overexpression of AngII and ET-1 can directly induce collagen I gene expression in the vasculature in vivo and, if so, whether their fibrogenic action follows identical or separate pathways. To address these issues, we performed this study, in which AngII and ET-1 were administered in control conscious transgenic mice with or without the concomitant administration of their respective receptor antagonists, candesartan and bosentan. We found that the stimulatory effect of AngII on the collagen I gene was blocked not only by its own receptor antagonist (as was expected) but, in addition, by the ET receptor antagonist bosentan (Figure 4) and that this interaction was not reciprocal (Figure 5). This result implies that the pathway leading from AngII to the collagen I gene requires an intermediate ET-1 action. Interestingly, the same dose of bosentan that markedly reduced the effect of AngII on procol2(I) had no effect on the transient increase of BP induced by the bolus injection of AngII (Figure 3), thus providing an additional element supporting the dissociation of the mechanisms controlling systemic hemodynamics from those involved in fibrogenesis.
Several recent studies indicate that, at least in some experimental models, AngII induces a local activation of ET-1 that is associated with the vascular remodelling. In agreement with this notion, ET-1 content or immunostaining was increased in the aorta, femoral artery, and kidney in the model of AngII-induced hypertension; antagonism of AngII receptors with losartan normalized endothelin levels (24,25). This model of hypertension is characterized by the hypertrophy of mesenteric resistance arteries, elevated levels of tissue ET-1 content, and the development of severe renal vascular fibrosis. Treatment of hypertensive animals with ET receptor antagonists preserved vascular geometry and markedly reduced the degree of renal lesions without affecting systemic BP (26). Similar observations were made in other experimental models of vascular injury in which the renin-angiotensin system is believed to be a major pathophysiologic factor such as congestive heart failure, uninephrectomized SHR, or chronic renal failure (5/6 nephrectomy) (27–29). In those studies, ET mRNA expression or peptide levels were increased; treatment with an ACE inhibitor or AT1 antagonist blunted the development of the pathology and was always accompanied by inhibition of ET activation. In support of the "AngII-induced activation of ET-1" hypothesis, we have observed that urinary excretion rate, mRNA expression, and peptide content of ET-1 in renal resistance vessels and glomeruli were increased in mice and rats treated with L-NAME and that treatment with an AT1 receptor antagonist inhibited this activation of the endothelin system (11,23).
TGF-ß is another known activator of collagen I gene expression in vitro, and several studies have associated the fibrogenic in vivo action of AngII to TGF-ß (5). One of the techniques used to block the in vivo action of TGF-ß is decorin administration. In this regard, exogenous administration of decorin mimicked the effect of chronic anti-TGF-ß antibody infusion by blunting the formation of extracellular matrix within the renal cortex and protecting rat kidneys from the development of glomerulonephritis (6). It is possible that, in certain cell types in vitro, increased concentrations of decorin can attenuate the action of other growth factors as well. However, this possibility appears unlikely, at least in the case of renal fibrosis, because endogenous overexpression of decorin in the skeletal muscle of rats by gene transfer technology inhibited the fibrogenic action of TGF-ß and protected kidneys against glomerulosclerosis (30), thus inciting the investigators to propose decorin as an efficient treatment against the TGF-ß-induced renal fibrosis.
In agreement with an AngII-TGF-ß-induced collagen I gene activation, AngII induced a rapid increase of TGF-ß mRNA levels in the renal cortex and aortas of our mice (Figure 7), and decorin blocked the effect of AngII on luciferase activity (Figure 5). The AngII-TGF-ß interaction does not appear to depend on systemic hemodymamics. In the L-NAME model of renal fibrotic hypertension for instance, TGF-ß mRNA expression was increased locally in the renal cortex (31); treatment with an ACE inhibitor, but not with hydralazine, reduced the exaggerated expression of TGF-ß and improved renal histology, despite a similar reduction of systolic BP with both treatments. Our results are in agreement with this hypothesis, because TGF-ß activated procol2(I) without increasing systolic pressure and decorin blocked the fibrogenic effect of AngII without altering the AngII-induced transient increase of BP (Figure 3). The issue of an interaction between TGF-ß and ET-1 in renal fibrosis remains still controversial. Thus, in two models of experimental fibrotic nephropathy (the streptozotocin-induced diabetes or the 5/6 nephrectomy), ETA/B antagonism had no effect on the exaggerated expression of TGF-ß or collagen IV and the progression of fibrosis in glomeruli and tubules (32,33). In other studies that used similar models of chronic renal failure (5/6 nephrectomy), bosentan markedly reduced extracellular matrix synthesis, protected renal structure, and improved the survival of 5/6 nephrectomized rats (19,20); regrettably, the effect of bosentan on TGF-ß expression was not studied. An interaction between ET-1, TGF-ß, and extracellular matrix was recently reported in vitro, where the ET-1-induced increase of fibronectin synthesis was blocked by anti-TGF-ß antibodies in cultured mesangial cells (34). Our results clearly indicate that both ET-1 and TGF-ß are important mediators of the AngII effect on collagen I gene but probably act though distinct pathways. Two pieces of evidence support this hypothesis: contrary to AngII, ET-1 did not increase TGF-ß mRNA levels and decorin had no effect on ET-1-induced activation of procol12. In a recent in vitro study, we investigated the intracellular signaling pathways that lead from AT1 receptor to collagen I gene activation in vascular tissues (35). We found that AngII produced a rapid activation of the MAP/ER kinase pathway that induced the formation of the AP-1 transcriptional complex, which in turn was involved in the activation of collagen I gene (35). In addition, we have observed that this pathway was distinct from the AngII-TGF-ß-collagen I interaction. To integrate our previous in vitro results with these presently obtained in vivo, we propose that ET-1 could be involved in the AngII-MAPK-AP-1 cascade. Recent data from another transgenic model, the rat that harbors both human renin and angiotensinogen genes, support this hypothesis (36). In that model of AngII-induced end-organ damage (mainly in heart and kidney), AP-1 expression and several genes regulated by this complex (such as ICAM-1 and VCAM-1) were locally overexpressed in the renal and cardiac tissues; treatment with bosentan, but not with hydralazine, improved albuminuria and renal injury and reduced mortality rates; these functional improvements were independent of BP effects and were associated to significant reduction of AP-1 (and AP-1-regulated genes) expression in the kidney. It would be interesting to investigate in future studies what are the intracellular pathways of the ET-1-induced activation of collagen I gene in the renal and vascular tissues.
In conclusion, we used a transgenic mouse model to investigate the fibrogenic action of AngII, ET-1, and TGF-ß in the aortic and renal cortical tissues. To our knowledge, this is among the first studies to have investigated interactions of these systems in in vivo protocols. Our results indicate a complex interaction among these three systems: AngII, ET-1, and TGF-ß can activate collagen I gene, but cooperation or synergism of ET-1 and TGF-ß are required and mediate the fibrogenic action of AngII. These data indicate the importance of the interactions between vasoconstrictors, such as AngII or ET-1, and growth factors, such as TGF-ß, in the mechanisms that control extracellular matrix synthesis; these interactions can have significant implications on the treatments of fibrotic complications associated with hypertension.
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2(I) collagen gene regulates expression of reporter genes in transgenic mice. J Cell Biol 134: 1333–1344, 1996
B, inflammation, and tissue factor in angiotensin II-induced end-organ damage. Hypertension 36: 282–290, 2000This article has been cited by other articles:
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, control; 
, AngII; 
, AngII + candesartan; 
, AngII + bosentan;, AngII + decorin. Values are means ± SEM of eight animals/condition; *P < 0.05 versus control; #P < 0.05 versus AngII.
