(Hypertension. 1996;27:885-892.)
© 1996 American Heart Association, Inc.
Articles |
Effects and Interactions of Endothelin-1 and Angiotensin II on Matrix Protein Expression and Synthesis and Mesangial Cell Growth
From the Renal Research Laboratory, Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain.
Correspondence to Jesús Egido, MD, Renal Research Laboratory, Fundación Jiménez Díaz, Avda Reyes Católicos 2, 28040 Madrid, Spain.
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Abstract |
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Abstract Mesangial cell growth and accumulation of extracellular matrix proteins constitute key features of progressive glomerular injury. Endothelin-1 (ET-1) and angiotensin II (Ang II), two potent vasoconstrictor agents, evoke a number of similar responses in mesangial cells. In rat mesangial cells, we compared ET-1 and Ang II effects on matrix protein production and cell proliferation as well as the potential interaction between the two hormones. When cells in 0.5% fetal calf serum were incubated for 24 hours with various concentrations of ET-1 or Ang II, both peptides stimulated, in a dose-dependent manner, fibronectin and type IV collagen mRNA expression, fibronectin synthesis, and mitogenesis. Incubation with specific receptor antagonists of both hormones demonstrated that endothelin subtype A (ETA) and angiotensin type 1 (AT1) receptors were involved. Preincubation of cells with two different protein kinase C inhibitors or with a neutralizing anti–transforming growth factor-ß antibody, but not an unrelated IgG, diminished the peptide-induced fibronectin synthesis. A dual interrelation seems to exist between ET-1 and Ang II. Thus, the AT1 receptor antagonist losartan and the angiotensin-converting enzyme inhibitors quinaprilat and captopril diminished the ET-1–mediated effects, whereas the ETA receptor antagonist BQ-123 diminished the Ang II–induced fibronectin synthesis and mesangial cell proliferation. Our results suggest that ET-1 and Ang II stimulate matrix protein synthesis and mesangial cell mitogenesis through ETA and AT1 receptors, respectively, by complicated mechanisms, implicating protein kinase C activation, synthesis of transforming growth factor-ß, and release of one peptide by the other. These data could be important for a better understanding of the participation of vasoactive substances in the pathogenesis of glomerulosclerosis.
Key Words: endothelin • angiotensin II • mesangial cells • matrix proteins • protein kinases • transforming growth factors • angiotensin-converting enzyme inhibitors
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The growth of MCs and production of matrix proteins have been associated with the appearance of proteinuria, glomerulosclerosis, and progressive renal failure in many animal models.1 ET-1 and Ang II, two potent vasoconstrictor peptides, act on MCs through specific receptors, inducing contraction and cell proliferation as well as increases in mRNA levels of proto-oncogenes and early genes.2 3 4 These facts suggest that both peptides could be excellent candidates for modification of mesangial matrix turnover. Nevertheless, although there is clear evidence that ET-1 is mitogenic for MCs,2 the effect of this peptide on matrix protein synthesis by cultured renal cells has not been clearly established. In rats with remnant kidney5 and immune complex nephritis,6 a correlation between urinary ET-1 excretion and the degree of glomerular injury has been observed. Treatment with a specific ETA receptor antagonist or an ETA/ETB antagonist prevented extracellular matrix accumulation and glomerulosclerosis in two models of kidney injury.6 7 Furthermore, severe lupus nephritis was reversed by a selective ETA receptor antagonist, with a downregulation of extracellular matrix gene expression.8
On the other hand, the intrarenal renin-angiotensin system seems to play an important role in glomerular cell growth and sclerosis.3 9 The administration of ACE inhibitors and Ang II receptor antagonists attenuated or reversed the development and progression of sclerotic lesions in various animal models of progressive glomerulosclerosis.3 9 Systemic infusion of Ang II to normal rats for 7 days induced proliferation of resident glomerular and interstitial cells and an important increase in the synthesis of fibronectin and interstitial collagens.10 Most authors agree that in vitro, Ang II stimulates the synthesis of matrix proteins in a number of cell types, including glomerular MCs.3 9 Hypertrophy or proliferation has been reported after Ang II stimulation of MCs from different species (reviewed in Reference 9), depending on culture conditions.
Profound connections seem to exist between ET-1 and Ang II. ET-1 was produced by cultured endothelial cells and MCs after Ang II stimulation.11 12 Furthermore, Ang II increases the production of ET-1 by human MCs and subsequently contributes to its mitogenic effects.13 On the other hand, ET-1 enhanced the conversion of Ang I to Ang II in pulmonary artery endothelial cells.14
The aim of this work was to study the effect of ET-1 on matrix protein production by cultured rat MCs compared with that of Ang II. The participation of PKC and TGF-ß in peptide-induced fibronectin synthesis was also determined. A correlation was established with the effect on MC proliferation under our culture conditions. Finally, we studied the potential interaction between the two peptides in fibronectin synthesis and MC proliferation.
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Methods |
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Isolation and Identification of MCs
MCs were isolated from glomeruli of male Sprague-Dawley rats weighing 100 to 150 g according to techniques previously described.15 Glomeruli were isolated from the renal cortex by differential sieving (150 and 50 µm) and posterior centrifugation. Thereafter, they were digested with type IA collagenase (Sigma Chemical Co); resuspended in RPMI-1640 supplemented with 20% FCS, 60 U/mL penicillin, 60 µg/mL streptomycin, and 2 mmol/L glutamine (BioWhittaker); and placed on Petri plates (Costar) for incubation at 37°C in an air atmosphere of 5% CO2 for 3 to 4 weeks. Under such conditions MCs began to spread after 7 to 14 days and the number of epithelial cells decreased. Around day 21, cell cultures obtained by this method were almost totally pure in MCs. Cells were identified by morphological and immunohistochemical methods. Assessed by phase-contrast microscopy, the cultures consisted of stellate or fusiform cells with prominent intracellular fibrillar structures. MCs showed positive staining for desmin and vimentin and for Thy-1 antigen and negative staining for factor VIII–related antigen and cytokeratin, excluding endothelial and epithelial contamination, respectively.16 Cells used for experiments had undergone one passage after initial seeding. Confluent MCs were washed with sterile, modified Dulbecco's medium (mmol/L: NaCl 137, KCl 2.6, Na2HPO4 8, KH2PO4 1.5, glucose 5.6, pH 7.2) and removed from cultured Petri plates by trypsin-EDTA (BioWhittaker) digestion. Dissociated cells were centrifuged, resuspended in RPMI-1640, and placed in Petri plates (Costar) for matrix protein expression experiments, in 24-well plates for immunoprecipitation experiments, and in 96-well plates for cell proliferation assays.
RNA Extraction and Northern Blot Hybridization
Total RNA from MCs was isolated by the acid guanidinium
thiocyanate/phenol/chloroform extraction method.17 The
purified RNA (10 µg per lane) was loaded onto a 1.2%
agarose/formaldehyde gel, electrophoretically separated, and
transferred to GeneScreen nylon membranes (New England Nuclear). RNA
was immobilized by exposure to UV light. Prehybridization,
hybridization, and washing were carried out according to the method
previously described.18 The cDNA probes pFH154 and
(
1)IV(pCIV-1-PE16) encoding the genes for fibronectin and (1)
type IV collagen, respectively, were provided by American Type Culture
Collection. The cDNA probes were labeled with a Nick translation kit
(Boehringer Mannheim). Membranes were exposed to X-Omat AR
films and intensifying screens at -70°C. Steady-state mRNA
transcript levels were quantified by scanning densitometry (Molecular
Dynamics). The equivalent loading of RNA was confirmed by hybridization
with 28S mRNA, a constitutively expressed gene, as internal
control.
Quantification of Fibronectin Biosynthesis
Fibronectin synthesis by MCs was measured as incorporation of
[35S]methionine (1000 Ci/mmol, ICN Radiochemicals) to
proteins immunoprecipitated with polyclonal anti-fibronectin
antibodies generated in our laboratory according to standard protocols.
MCs were incubated for 24 hours with different stimuli in a final
volume of 1 mL RPMI-1640 with 0.5% FCS and only 5% of the usual
concentration of methionine and were supplemented with 20 µCi/mL
[35S]methionine. After incubation, supernatants and cells
were collected. From all samples, 20 µL was taken for determination
of DNA content, and equal amounts of DNA were immunoprecipitated.
Immunoprecipitation, electrophoresis, and
autoradiography were performed by the
anti-fibronectin antibody as previously described.19
Laser densitometry was done on the autoradiographs, and the data are
expressed as the percentage of [35S]methionine
incorporated by MCs in the same experiment under basal conditions
(basal was taken as 100%).
The participation of PKC and TGF-ß in the peptide-induced fibronectin synthesis was determined with two PKC inhibitors, staurosporine (10-7 mol/L) and H-7 (10-6 mol/L) (Sigma), and a polyclonal rabbit anti–TGF-ß1,2,3 antibody (Immunogenex), respectively.
In some experiments, MCs were preincubated for 1 hour with different concentrations of the ACE inhibitors quinaprilat (Parke-Davis) and captopril (Bristol-Myers Squibb). In other experiments, before addition of the substances to be tested, MCs were preincubated for 1 hour with the Ang II receptor antagonists losartan (an AT1 receptor antagonist, DuPont Merck) and PD 123177 (an AT2 receptor antagonist, Parke-Davis) or the endothelin receptor antagonists BQ-123 (an ETA receptor antagonist, Neosystem) and IRL1038 (an ETB receptor antagonist, Peninsula Laboratories). The final concentration of these receptor antagonists was 10-6 mol/L.
Cell Proliferation Assays
MC proliferation was determined by measurement of
[3H]thymidine incorporation (70 Ci/mmol, ICN
Radiochemicals). MCs were subcultured in 96-well plates (Costar) and
grown to 60% to 70% confluence in RPMI-1640 medium containing
20% FCS. They were subsequently starved for 2 days in 200 µL medium
containing 0.5% FCS (changed every day) to make them quiescent. At
this point control medium, ET-1, Ang II, or serum was added (time=0) to
RPMI-1640 plus 0.5% FCS, and after an 18-hour incubation the cells
were pulsed for 6 hours more with 1 µCi per well
[3H]thymidine. Cells were washed twice with ice-cold
phosphate-buffered saline and harvested with a semiautomatic cell
harvester (Skatron) and collected on glass-fiber filter strips.
[3H]Thymidine incorporation was measured in a liquid
scintillation analyzer (Beckman Instruments Inc). In some
experiments, before addition of the substances to be tested, MCs were
preincubated for 1 hour with quinaprilat, captopril, or the endothelin
and Ang II receptor antagonists, as mentioned above.
Statistics
All values are mean±SE. Comparisons between means of
multiple groups were analyzed by one-way ANOVA and
Scheffé's multiple comparison test.
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Results |
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Effect of ET-1 and Ang II on Fibronectin and Type IV Collagen mRNA Expression
We tested whether ET-1 was able to induce the gene expression of extracellular matrix proteins in MCs using Northern blot hybridization experiments. We then compared this effect with that observed with Ang II in the same experimental conditions. ET-1 (10-8 mol/L) increased matrix protein expression. The fibronectin mRNA level induced by ET-1 was higher at 24 than 18 hours (2.3- versus 1.5-fold) (Fig 1
, top and bottom
left). However, type IV collagen mRNA increased almost
3-fold at 18 hours and decreased to 1.5-fold at 24 hours (Fig 1, top
and bottom left). Ang II (10-7 mol/L)
increased both fibronectin and (1) type IV collagen mRNA expression
at 18 hours of stimulation and maintained it up to 24 hours (Fig 1, top
and bottom right).
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Effect of ET-1 and Ang II on Fibronectin Synthesis
As shown in Fig 2, both ET-1 and Ang II induced an
increase in fibronectin synthesis in a dose-dependent manner for
the range studied, the effect of ET-1 being greater than that of Ang II
at equimolar concentrations (ie, basal, 100%;
10-8 mol/L ET-1, 143±4%
[P<.05 versus basal]; 10-8
mol/L Ang II, 130±3% [P<.05 versus basal and ET-1];
n=8). The fibronectin synthesis induced by
10-8 mol/L ET-1 was significantly
diminished in the presence of the ETA receptor
antagonist BQ-123 (10-6
mol/L, Fig 3A). No changes were noted in the fibronectin
synthesis induced by ET-1 in the presence of the ETB
receptor antagonist IRL1038
(10-6 mol/L, Fig 3A). The AT1
receptor antagonist losartan
(10-6 mol/L) significantly suppressed the
Ang II–induced fibronectin synthesis (Fig 3B).
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Neither ET-1 nor Ang II alone altered [35S]methionine incorporation, suggesting that in our experimental conditions no significant stimulation of total protein synthesis occurred (data not shown).
Effect of PKC Inhibition on Fibronectin Synthesis Induced by ET-1
and Ang II
Our next objective was to study the role of PKC in the fibronectin
synthesis induced by ET-1 and Ang II. MCs were preincubated for 30
minutes with staurosporine
(10-7 mol/L) or H-7
(10-6 mol/L), two different PKC
inhibitors, and thereafter stimulated with ET-1 or Ang II
(10-8 mol/L) for 24 hours. As can be seen
in Fig 4, staurosporine and H-7
significantly inhibited the fibronectin synthesis induced by ET-1 and
Ang II. Staurosporine abolished the fibronectin synthesis
induced by both peptides, whereas H-7 inhibited Ang II– and
ET-1–induced fibronectin synthesis around 77% and 100%,
respectively.
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Effect of Anti–TGF-ß Antibodies on Fibronectin Synthesis Induced
by ET-1 and Ang II
To determine the role of TGF-ß in the fibronectin synthesis
induced by ET-1 and Ang II, we preincubated cells with a polyclonal
anti–TGF-ß antibody before stimulation with the peptides. The
presence of 10 µg/mL anti–TGF-ß antibody inhibited the fibronectin
synthesis induced by ET-1 and Ang II
(10-8 mol/L) to below basal values (Fig 5). Anti–TGF-ß antibody alone also inhibited
fibronectin synthesis. No changes were observed when the cells were
incubated in the presence of an unrelated IgG.
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Effect of ACE Inhibitors and Losartan on
Fibronectin Synthesis and MC Proliferation Induced by
ET-1
We noted that both ET-1 and Ang II plated in subconfluent wells
and in the presence of 0.5% FCS increased the growth of adult rat MCs
for 24 hours. Both effects were dose dependent, the maximal effect
being around 49% and 52%, respectively, of that seen with 20% FCS.
The Ang II–induced proliferation was inhibited by losartan but
not by PD 123177 (10-8 mol/L Ang II,
1887±398 cpm per well; Ang II plus 10-6
mol/L losartan, 1096±96 [P<.05 versus Ang II];
Ang II plus 10-6 mol/L PD 123177,
1643±94; n=5). Ang II receptor antagonists alone had no
significant effect on [3H]thymidine incorporation (basal,
1000 cpm per well; losartan, 1355±342;
10-6 mol/L PD 123177, 1212±169; n=5,
P=NS versus basal).
As can be seen in Fig 6, when MCs were stimulated for 24
hours with 10-8 mol/L ET-1 in the
presence of 10-6 mol/L losartan,
both fibronectin synthesis (Fig 6A) and the proliferation (Fig 6B)
induced by ET-1 were significantly inhibited. Different concentrations
of quinaprilat diminished both ET-1–induced fibronectin synthesis (Fig 7A) and MC proliferation (Fig 7B) in a
dose-dependent manner for the range studied. Fibronectin synthesis
was not changed by quinaprilat alone (ie, basal, 100%;
10-6 mol/L quinaprilat, 97±24%; n=4,
P=NS), although it induced a slight but not significant
increase in MC proliferation (ie, basal, 1000 cpm per well;
10-6 mol/L quinaprilat, 1542±307; n=8,
P=NS). Similar results were obtained when MCs were incubated
with another ACE inhibitor, captopril, plus ET-1 (data not
shown).
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Effect of BQ-123 on Fibronectin Synthesis and MC Proliferation
Induced by Ang II
We investigated the idea that ET-1 could play a role in the effect
observed with Ang II on cultured rat MCs. Similar to fibronectin
synthesis, the ET-1–induced proliferation was inhibited by BQ-123 but
not by IRL1038 (10-8 mol/L ET-1,
2108±495 cpm per well; ET-1 plus 10-6
mol/L BQ-123, 1220±146 [P<.05 versus ET-1]; ET-1 plus
10-6 mol/L IRL1038, 1796±236; n=3-8).
Neither BQ-123 nor IRL1038 alone had any significant effect on MC
proliferation in our experimental conditions (basal, 1000 cpm per well;
10-6 mol/L BQ-123, 1256±215;
10-6 mol/L IRL1038, 1004±31; n=3,
P=NS versus basal). MCs were preincubated with BQ-123
(10-6 mol/L) before a 24-hour stimulation
with Ang II. The Ang II–induced fibronectin synthesis was
inhibited by 10-6 mol/L BQ-123 by
approximately 40% (Fig 8A). Similar results were
obtained when we measured Ang II–induced [3H]thymidine
incorporation, the inhibition of 10-6
mol/L BQ-123 being approximately 79% (Fig 8B).
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We also stimulated MCs with Ang II in the presence of quinaprilat.
Quinaprilat (10-6 mol/L) significantly
decreased Ang II–induced fibronectin synthesis (Fig 8B
); similar
results were observed when we measured MC proliferation (Fig 8A).
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Discussion |
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Besides the vasoactive properties of ET-1, its effects on cell growth have also been extensively studied.2 However, despite suggestions in previous in vivo studies about the effect of endothelins on extracellular matrix protein production in renal cells,6 7 8 little information exists about such an effect. We undertook the present study to characterize the effects of ET-1 on extracellular matrix formation by MCs. Since MCs possess receptors for ET-1 and Ang II and both hormones evoke a number of similar intracellular responses, we studied the Ang II effects on matrix production for comparison. We also assessed the possible interaction between the two peptides on fibronectin synthesis and cell proliferation.
In the present work, we have observed that ET-1 stimulated fibronectin and type IV collagen production by cultured rat MCs through the activation of the ETA receptor. Although rat MCs possess ETA and ETB receptors,2 ligand binding studies have shown that they express only a functional ETA receptor.20 Under our experimental conditions, Ang II closely mimicked the effects of ET-1 on extracellular matrix production through its AT1 receptor. In recent studies, only the AT1 receptor was demonstrated in human fetal and adult MCs in vitro.21 22
We also studied the role of PKC, which lies between the possible mechanisms implicated in matrix protein synthesis induced by both vasoactive hormones. In rat MCs, both peptides activate phospholipase C, leading to PKC activation.2 3 Previous investigations have demonstrated that the growth effects of ET-1 and Ang II are PKC dependent.2 23 Although we have not obtained direct evidence of PKC activation, experiments with the PKC inhibitors staurosporine and H-7 suggest that fibronectin synthesis occurs through this pathway.
Among the cytokines that may participate in matrix protein regulation by ET-1 and Ang II, TGF-ß appears to be a key candidate. Ang II increases the production of TGF-ß,23 24 a growth factor implicated in the pathogenesis of fibrosis in several tissues.25 Furthermore, in different models of vascular and glomerular injury, the augmentation in mRNA expression of renin, ACE, and preproET-1 was accompanied by an increase in TGF-ß synthesis.18 26 27 28 29 30 31 32 As shown in "Results," the presence of a neutralizing anti–TGF-ß antibody in the culture medium, but not an unrelated IgG, decreased the synthesis of fibronectin induced by ET-1 and Ang II, suggesting a role for the autocrine production of TGF-ß. The mechanism by which both peptides could induce TGF-ß expression is not known. ET-1 and Ang II elicit gene expression of c-fos and c-myc,2 33 whose protein products bind to activator protein-1 (AP-1) sites that can activate gene transcription.34 It is known that the promoter of the TGF-ß gene contains AP-1 sites that can modulate TGF-ß gene expression.35 Recent data suggest that in cultured MCs, PKC signals TGF-ß bioactivity and the fibronectin synthesis observed in response to Ang II and other vasoactive substances such as thromboxane.36
It has been demonstrated that the interaction between ET-1 and Ang II is important for the regulation of glomerular function, matrix turnover, and cell growth (reviewed in Reference 9). In cardiomyocytes, aortic cells, and proliferating human MCs, the ET-1 generated on stimulation with Ang II seems responsible for some of the evoked effects attributed to the latter peptide.13 37 38 On the other hand, ET-1 can induce ACE activity in cultured bovine pulmonary artery endothelial cells.14 Therefore, in cultured rat MCs, we studied the potential dual interaction between ET-1 and Ang II on fibronectin synthesis and cell growth. In our experimental conditions, ET-1 and Ang II increased rat MC proliferation in a dose-dependent manner and at a similar rate. As in fibronectin synthesis, cell proliferation elicited by ET-1 and Ang II was via ETA and AT1 receptors, respectively. The mitogenic effect of ET-1 had been previously described in different cell types, including MCs.2 However, both hypertrophy and proliferation have been reported after Ang II stimulation, probably depending on cell culture conditions, the presence of serum cofactors, and/or the use of MCs with a different origin.
Previous data have demonstrated that Ang II, in both the absence and presence of FCS, stimulates ET-1 secretion in cultured rat and human MCs.12 13 Furthermore, the latter authors have also shown that ET-1 modulated the Ang II–induced mitogenesis of human MCs.13 In the present article, we have noted that the Ang II–induced fibronectin synthesis and proliferation in rat MCs may be blocked by the specific ETA receptor antagonist BQ-123, further suggesting a role for endogenous ET-1 in those phenomena.
On the other hand, the presence of the specific AT1 antagonist losartan and the ACE inhibitors quinaprilat and captopril decreased ET-1–induced fibronectin synthesis and mitogenesis, suggesting though not yet proving that part of the effect of ET-1 is mediated through newly generated Ang II. Neither quinaprilat nor captopril alone had any effect on fibronectin synthesis and cell proliferation. The absence of an antimitogenic effect of ACE inhibitors on human MCs under serum-free or quiescent culture conditions has been previously described by Bakris et al,39 who found that in such conditions, there was no ACE activity in the conditioned medium. The same investigators also showed that the attenuation of Ang II–induced MC proliferation observed with ACE or AT1 receptor antagonists was associated with decreased synthesis of ET-1.39
The mechanisms by which ACE inhibitors may inhibit the ET-1–mediated effects are unknown and still speculative. ACE inhibitors could exert other effects different from their action on converting enzyme activity. In isolated cardiomyocytes, quinaprilat abolished protein synthesis and mRNA expression of early growth response gene-1 (egr-1) induced by ET-1.40 Thus, the [Ca2+]i increase induced by ET-1, Ang II, platelet-derived growth factor, and vasopressin in MCs was inhibited by captopril and enalapril.41 In vivo, quinapril administration to dogs abolished the hemodynamic alterations induced by intrarenal infusion of ET-1.42 Furthermore, ACE inhibitors decreased the ET-1 mRNA expression in different models of renal injury, such as renal mass reduction in the spontaneously hypertensive rat,43 membranous nephropathy,44 and immune complex nephritis (unpublished data, 1995).
Collectively, our results show that in cultured MCs vasoactive substances such as ET-1 and Ang II induce an increase in the gene expression and synthesis of matrix proteins and cell proliferation through ETA and AT1 receptors, respectively. Furthermore, we have shown that the effects of these peptides on MCs are very complex, probably implicating the release of one hormone by the other and the synthesis of growth factors such as TGF-ß. The striking inhibitory effect of ACE inhibitors in ET-1–induced fibronectin synthesis and cell proliferation enlarges the therapeutic indications of ACE inhibitors in those situations in which ET-1 has been implicated. These findings could be important for a better understanding of the mechanisms of chronic damage and sclerosis in different kidney diseases.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported partially by grants from Fondo de Investigaciones Sanitarias de la Seguridad Social (FIS) (92/790, 93/834, and 94/0370); Ministerio de Educación y Ciencia (92/0042); Parke-Davis, Spain; and Fundación Iñigo Alvarez de Toledo. D.G.-G., M.R.-O., M.O., and M.J.L.-A. are fellows of the Fundación Conchita Rábago. R.L. is a fellow of FIS. E.G. is a postdoctoral fellow of the Fundación Jiménez Díaz. We thank Dr Alberto Ortiz for reading the manuscript and Liselotte Gulliksen for her excellent secretarial assistance.
Received June 26, 1995; first decision August 29, 1995; accepted January 8, 1996.
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