Nephrology Research Unit, Mayo Clinic/Foundation, Rochester, Minnesota 55905
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ABSTRACT |
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We examined whether nitric oxide-generating agents influence expression of heme oxygenase-1 (HO-1) in renal proximal tubular epithelial cells, LLC-PK1 cells, and the mechanisms underlying any such effects. In sublytic amounts, the nitric oxide donor sodium nitroprusside induced HO-1 mRNA and protein and HO activity in a dose-dependent and time-dependent fashion; this induction was specific for nitric oxide since the nitric oxide scavenger carboxy-2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide significantly reduced such induction. The induction of HO activity by sodium nitroprusside, or by another nitric oxide donor, spermine NONOate, was markedly reduced by the iron chelator deferoxamine. Two different thiol-containing agents, N-acetylcysteine and dithiothreitol, blunted such induction of HO by nitric oxide. Downstream products of nitric oxide, such as peroxynitrite or cGMP, were not involved in inducing HO. In higher concentrations (millimolar amounts), sodium nitroprusside induced appreciable cytotoxicity as assessed by lactate dehydrogenase (LDH) release and lipid peroxidation, and both of these effects were markedly reduced by deferoxamine. Inhibition of HO did not affect the cytotoxic effects (measured by LDH release) of sodium nitroprusside. We thus provide the novel description of the induction of HO-1 in renal proximal tubular epithelial cells exposed to nitric oxide donors and provide the first demonstration in kidney-derived cells for the involvement of a redox-based mechanism in such expression. We also demonstrate that, in LLC-PK1 cells exposed to nitric oxide donors, chelatable iron is involved in eliciting the HO-1 response observed at lower concentrations of these donors, and in mediating the cytotoxic effects of these donors when present in higher concentrations.
cell injury; oxidant stress; kidney; deferoxamine
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INTRODUCTION |
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THE INDUCIBLE ISOFORM of nitric oxide synthase, iNOS, generates copious amounts of nitric oxide from L-arginine (14, 15). Such generation of nitric oxide occurs in models of renal injury and is incriminated in the injury that ensues (10, 14). The evidence for this involvement of iNOS and attendant nitric oxide-dependent toxicity is particularly persuasive in in vitro models of renal hypoxia-reoxygenation injury and in in vivo models of renal ischemia-reperfusion injury (7, 14, 20, 21, 29, 30, 40). Nitric oxide, in relatively large amounts, can induce cell injury through multiple mechanisms that may involve the capacity of nitric oxide to generate peroxynitrite, to nitrosylate thiol groups, and to impair iron sulfur clusters in proteins (5, 10, 14, 15, 17); intracellular targets susceptible to the damaging effects of nitric oxide include the plasma membrane, the cytoskeleton, the mitochondrion, and the nucleus (5, 10, 14, 15, 17).
Heme oxygenase-1 (HO-1), like iNOS, is an enzyme system that is widely inducible in cells, and HO-1 and iNOS share overlapping stimuli (22, 32). HO is the rate-limiting enzyme in the degradation of heme, facilitating the opening of the heme ring and its conversion to biliverdin, in the course of which carbon monoxide evolves, and iron is released; iron, in turn, fosters the synthesis of ferritin while biliverdin is subsequently converted to bilirubin (22, 32). The isozyme HO-1 is readily induced by heme, oxidants, lipopolysaccharide, cytokines, irradiation, heavy metals, and other stressors, many of which also stimulate iNOS. The HO-1 system bears other similarities to the iNOS system besides responsivity to similar inducers: HO-1 and iNOS are both heme-containing enzymes that generate gaseous products (carbon monoxide in the case of HO-1 and nitric oxide in the case of nitric oxide synthase); carbon monoxide and nitric oxide exert quite similar biological actions (22, 32).
Given the rapidly emerging recognition of iNOS as a mediator of proximal tubular injury, and the recognition that in models of renal injury in which HO-1 has been studied such induction occurs mainly in the tubulointerstitial compartment of the kidney (1, 3, 19, 27, 39), we examined whether the exposure of proximal tubules to nitric oxide-generating systems induces HO-1 and explored the basis for any such induction. We demonstrate the novel finding that nitric oxide induces HO-1 in renal tubular epithelial cells, and we uncover the importance of oxidative stress in general and the role of iron, in particular, for such induction of HO-1 by nitric oxide.
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MATERIALS AND METHODS |
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Reagents employed. Deferoxamine mesylate (DFO), N-acetylcysteine (NAC), dithiothreitol (DTT), superoxide dismutase (SOD), catalase, sodium nitroprusside, 3-morpholinosydnonimine (SIN-1), and 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ) were obtained from Sigma (St. Louis, MO), whereas spermine NONOate and carboxy-2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (carboxy-PTIO) were obtained from Calbiochem (San Diego, CA). Sodium nitroprusside, spermine NONOate, SIN-1, carboxy-PTIO, DFO, NAC, DTT, SOD, and catalase were freshly prepared in cell culture media or Hanks' balanced salt solution (HBSS) as indicated. ODQ was dissolved in DMSO and diluted in cell culture media. The concentrations of DMSO were <0.1%.
Cell culture. LLC-PK1 cells were obtained from American Type Culture Collection (Rockville, MD) and were grown in DMEM (GIBCO-BRL, Gaithersburg, MD) at 37°C in 95% air and 5% carbon dioxide, as previously described (2, 26). The medium contained 1 mM sodium pyruvate and was supplemented with 10% FCS, 100 U/ml penicillin, and 100 µg/ml streptomycin. Cells were studied as a confluent monolayer in all experiments.
Determination of HO activity and expression of HO-1 mRNA and
protein in LLC-PK1 cells.
HO activity was measured by bilirubin generation in microsomes isolated
from LLC-PK1 cells, as described previously
(2). Cells were washed, scraped with a rubber policeman,
and centrifuged at 1,000 g for 10 min at 4°C. The cell
pellet was suspended in phosphate (100 mM) buffer (pH 7.4) and
sonicated on ice before centrifugation at 12,000 g for 10 min at 4°C. The supernatant was centrifuged at 100,000 g
for 60 min at 4°C. The pellet was suspended in phosphate buffer (pH
7.0) containing 2 mM MgCl2 and designated as the microsome
fraction. An aliquot of the microsomal fraction was added to the
reaction mixture (400 µl) containing rat liver cytosol (2 mg of
cytosolic protein), hemin (20 µM), glucose 6-phosphate (2 mM),
glucose-6-phosphate-dehydrogenase (0.2 units), and NADPH (0.8 mM) and
was incubated for 1 h at 37°C in the dark. The formed bilirubin
was extracted with chloroform, and the change in optical density at
464-530 nm was measured (extinction coefficient, 40 mM1 · cm
1 for bilirubin).
HO activity is determined as picomoles of bilirubin formed per 60 min
per milligram protein. To characterize the dose-dependent and
time-dependent effects of sodium nitroprusside on HO activity, we
report HO activity in absolute terms in these studies. In subsequent studies in which various relevant experimental conditions were employed
so as to determine the basis for such inductive effects, such
protocols, of necessity, were undertaken on different days, and the
data were pooled for that protocol. In such studies, as previously
employed by others (9), data for HO activity are reported
as fold-increase.
Cytotoxicity assay. Cytotoxicity of nitric oxide donors on LLC-PK1 cells was determined by the lactate dehydrogenase (LDH) release assay, as previously described (26, 28). In additional studies, we tested the effect of the inhibitor of HO, tin protoporphyrin (20 µM), on the cytotoxicity of sodium nitroprusside in LLC-PK1 cells using the LDH release assay.
Lipid peroxidation. Lipid peroxidation of LLC-PK1 cells was determined by the assay based on the determination of thiobarbituric acid reactive substances (TBARS), as previously described (26).
Statistical analysis. Data are expressed as means ± SE. The Student's t-test was employed for comparisons involving two groups, whereas, for comparisons involving more than two groups, ANOVA and the Student-Newman-Keuls test were applied. All results are considered significant at P < 0.05.
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RESULTS |
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We first demonstrate a dose-dependent and time-dependent response
for the induction of HO-1 in cells exposed to the nitric oxide donor,
sodium nitroprusside. As shown in Fig. 1,
induction of both HO-1 mRNA and protein occurs in a dose-dependent
fashion in studies performed after exposure of LLC-PK1
cells for 4 h and 6 h, respectively; HO-2 mRNA expression is
relatively unchanged in cells exposed to these concentrations of sodium
nitroprusside. The time course for such induction of HO-1 in response
to 0.5 mM sodium nitroprusside is shown in Fig.
2; we selected this concentration of
sodium nitroprusside in this and subsequent studies since this concentration is associated with no detectable cytotoxicity, as measured by the LDH release assay. This concentration of sodium nitroprusside led to a maximal expression of HO-1 mRNA at 4 h and
maximal expression of HO-1 protein at 12 h after such exposure. This induction of HO-1 mRNA and protein was accompanied by robust expression of HO activity, as shown in Fig.
3; a dose-dependent induction of HO
activity was again observed (Fig. 3A), and, at a
concentration of 0.5 mM sodium nitroprusside, the activity of HO was
maximal at 12 h (Fig. 3B).
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To examine the specificity of nitric oxide as the inducing stimulus for
the expression of HO-1, we undertook studies utilizing the specific
scavenger for nitric oxide, carboxy-PTIO (4). As shown in
Fig. 4A, the presence of this
nitric oxide scavenger reduced the expression of HO-1 mRNA and HO-1
protein. A significant reduction in sodium nitroprusside-induced HO
activity was also evidenced in the presence of carboxy-PTIO, as shown
in Fig. 4B.
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To determine the mechanisms accounting for such inductive effects of
sodium nitroprusside on HO activity, we considered the possibility that
iron and oxidative processes may provide the stimulus for such
expression. As shown in Fig. 5, the iron
chelator DFO was remarkably potent in attenuating the induction of HO
activity in response to sodium nitroprusside. Such reduction was
observed with concentrations of DFO as low as 0.01 mM, whereas HO
activities in the presence of 0.1 and 1 mM DFO were increased only
marginally, albeit significantly so, from control values. DFO alone
exerted no significant effect on HO activity (data not shown).
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We also examined such effects of DFO in the response to another nitric oxide-generating agent, spermine NONOate (23). This distinct nitric oxide-generating agent also induced HO activity, an effect that was again reduced in the presence of DFO (2.85 ± 0.10 vs. 1.81 ± 0.10-fold increase in HO activity, n = 3 in each group, P < 0.05). Thus HO activity is induced in response to a different nitric oxide-generating agent, an effect that is again attenuated by the iron chelator DFO.
We also considered the possibility that cellular thiols may influence
the induction of HO by sodium nitroprusside. These data are shown in
Fig. 6. The increase in HO activity in
the control setting in response to sodium nitroprusside was
significantly reduced when such induction was studied in the presence
of two different thiol agents, namely NAC and DTT. Thus thiol reagents significantly reduced the capacity of sodium nitroprusside to induce HO
activity.
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Nitric oxide interacts with superoxide to generate peroxynitrite
(5, 15), and this oxidant may contribute to some of the
cellular effects of nitric oxide. In settings in which peroxynitrite is
incriminated as a mediator for the cellular effects of nitric oxide,
reduction in the prevailing cellular levels of superoxide anion by SOD
reduces the observed cellular effect. As our first step in examining
the potential involvement of peroxynitrite, we studied the effect of
SOD on sodium nitroprusside-induced HO activity. As demonstrated in
Fig. 7, at lower concentrations (100 U/ml), SOD had no effect on the induction of HO by sodium
nitroprusside, whereas at the higher concentrations (200 U/ml), SOD
enhanced such induction of HO by sodium nitroprusside.
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That SOD failed to downregulate sodium nitroprusside-induced HO
activity suggested that peroxynitrite is not involved in the induction
of HO by sodium nitroprusside. To examine this possibility further, we
utilized another agent, SIN-1. SIN-1 generates both peroxynitrite and
nitric oxide in the presence of complex media such as complete cell
culture media, whereas, in the presence of simple buffered solutions,
SIN-1 is incapable of generating nitric oxide and generates, largely,
peroxynitrite (5). As demonstrated in Fig.
8, induction of HO activity in response
to sodium nitroprusside and SIN-1 was observed in the presence of the
full cell culture media, effects that may arise from either nitric
oxide or peroxynitrite. However, in the presence of HBSS, sodium
nitroprusside but not SIN-1 induced HO activity. In this latter
circumstance, SIN-1 likely generates peroxynitrite without concomitant
nitric oxide, and thus the failure of HO-1 to be induced by SIN-1 in
HBSS demonstrates that, at least under these conditions, peroxynitrite
may not serve as an inductive stimulus.
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We then examined whether cGMP, which transmits many of the effects of nitric oxide, was involved in such induction of HO activity. We made use of the inhibitor of soluble guanylate cyclase, namely ODQ, which prevents the generation of cGMP induced by nitric oxide (13). However, in our studies of sodium nitroprusside-induced HO activity, the concomitant presence of ODQ did not influence such induction of HO activity; increments in HO activity in the absence and presence of ODQ were not significantly different [4.09 ± 0.50 vs. 4.31 ± 0.45, n = 4 in each group, P = not significant (NS)]; ODQ alone exerted no effect on HO activity (data not shown).
Given the critical role of chelatable iron in the cellular HO-1
response to sodium nitroprusside, we questioned whether the cytotoxicity that is induced by larger doses of sodium nitroprusside is
also dependent on chelatable iron. As demonstrated in Fig. 9, sodium nitroprusside exerts
dose-dependent cytotoxicity, as reflected by the LDH release assay, and
such cytotoxicity is markedly attenuated in the presence of the iron
chelator DFO. Additionally, such an iron chelator also prevented
oxidative stress associated with such toxicity; the latter was assessed
by lipid peroxidation measured by the TBARS assay (Fig.
10).
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Because millimolar amounts of sodium nitroprusside are cytotoxic, we determined whether the induction of HO-1 in cells exposed to sodium nitroprusside is functionally significant. We thus concomitantly treated sodium nitroprusside-exposed cells with the inhibitor of HO, tin protoporphyrin (20 µM). In these studies, cytotoxicity (measured by the LDH release assay), induced by millimolar amounts of sodium nitroprusside, was not significantly altered by tin protoporphyrin when concentrations of sodium nitroprusside employed were 2 mM (30 ± 1 vs. 35 ± 2%, n = 3 in each group, P = NS), 4 mM (60 ± 2 vs. 59 ± 1%, n = 3 in each group, P = NS), and 8 mM (81 ± 2 vs. 80 ± 2%, n = 3 in each group, P = NS).
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DISCUSSION |
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Our data demonstrate robust induction of HO-1 in renal tubular epithelial cells after exposure of these cells to nitric oxide-generating agents. Indeed, the increment in HO activity in response to such agents is among the most vigorous encountered in the course of studies examining inducers of HO-1. Prior studies have demonstrated the capacity of nitric oxide donors to induce HO-1 in diverse nonrenal cells, including endothelial and smooth muscle cells (12, 16, 37), whereas studies in the kidney have demonstrated such inductive effects of nitric oxide-generating agents on mesangial cells (8, 34). Thus our work provides new evidence that such inductive effects are applicable to the tubular compartment.
We embarked on this examination of the capacity of nitric oxide to induce HO-1 given the rapidly accruing evidence that induction of iNOS and attendant generation of large amounts of nitric oxide contribute importantly to acute renal tubular epithelial cell injury (10, 14). Because in models of acute renal failure, the renal tubular compartment is the site of injury targeted by nitric oxide, we questioned whether this compartment, when exposed to nitric oxide, can respond by recruiting HO-1. Additionally, in models of acute renal injury (whether glomerular or tubular) in which induction of HO-1 is described, such induction occurs, mainly, in the renal tubular epithelium (1, 27, 39); in some instances, HO-1 is expressed in glomerular macrophages (24), in interstitial macrophages (3), and in the peritubular interstitium (19).
We demonstrate that pharmacologically distinct nitric oxide donors are capable of inducing HO-1 and that such induction was elicited by noncytolytic doses of these nitric oxide donors. That nitric oxide per se contributed to such induction was demonstrated by studies using carboxy-PTIO, a scavenger for nitric oxide (4). Such effects of nitric oxide were not channeled through cGMP, since in protocols that utilized ODQ (an inhibitor of soluble guanylate cyclase; see Ref. 13) the induction of HO-1 by sodium nitroprusside was unaltered by the concomitant presence of ODQ.
In prior studies in mesangial cells that demonstrate the induction of HO-1 mRNA by nitric oxide donors, it was speculated that such induction of HO-1 is independent of the redox status of nitric oxide (8). The cellular mechanisms and the biochemical intermediates, however, accounting for such induction of HO-1 remain uncertain (8). In another study of mesangial cells, it was demonstrated that the nitric oxide donor S-nitrosoglutathione and a redox cycling compound, independently or in unison, induced HO-1 (34). However, the role of cellular redox in mediating such inductive effect of nitric oxide donors on HO-1 expression in mesangial cells was not explored (34). We decided to explore redox-related mechanisms as a possible basis for nitric oxide-induced HO-1 expression in view of the persuasive body of data demonstrating the role of cellular redox in influencing expression of HO-1 (22, 32). Indeed, studies in vascular smooth muscle cells raised the possibility that cellular thiols influence the expression of HO-1 by sodium nitroprusside (16). Our studies provide the first demonstration in kidney-derived cells that cellular redox critically contributes to the induction of HO-1 by sodium nitroprusside; such induction of HO-1 in LLC-PK1 cells was significantly reduced by an iron chelator, even in low concentrations, and was attenuated by the presence of two distinct thiol agents.
Our findings differ in some respects from those derived in endothelial cells in that, in these latter studies (25), a higher concentration of DFO elicited less of an inhibitory effect on sodium nitroprusside-induced expression of HO activity (25). Additionally, our findings regarding the lack of involvement of peroxynitrite in nitric oxide-induced expression of HO-1 in LLC-PK1 cells also contrast with findings derived from studies of endothelial cells (12). These latter studies concluded that peroxynitrite is an important intermediate in the induction of HO-1 by nitric oxide (12). In our studies, enzymatic scavengers of the superoxide anion increased such induction; if peroxynitrite was involved as an intermediary in the cellular system we studied, such scavengers should reduce this induction of HO-1. This effect of SOD argues against involvement of peroxynitrite in mediating this action of sodium nitroprusside in LLC-PK1 cells. Additional evidence against peroxynitrite was provided by studies using SIN-1 in the presence and absence of full cell culture medium and HBSS; in the former circumstance SIN-1 generates nitric oxide and peroxynitrite and marked upregulation of HO-1 is observed, whereas, in the presence of simple buffered solutions, SIN-1 generates peroxynitrite without concomitant nitric oxide (5); in this latter setting using HBSS, HO-1 is not induced. Moreover, this lack of involvement of peroxynitrite in the induction of HO-1 indicates that scavenging of peroxynitrite by DFO, an action of DFO described in other settings (5, 15), cannot be the basis for the efficacy of DFO in preventing induction of HO-1 by nitric oxide donors we describe in the present study.
Our studies also demonstrate that the toxicity of these nitric oxide donors in this model system is critically dependent on iron. Using the LDH release and the TBARS assays to assess nitric oxide-induced cell injury, we demonstrate that DFO markedly reduces such effects of sodium nitroprusside. Thus the mechanism of injury and the response to injury, (in this case, HO-1) in LLC-PK1 cells, exposed to increasing concentrations of the nitric oxide donor, sodium nitroprusside, are both dependent upon chelatable iron.
Because induction of HO-1 may influence cellular levels of iron, it is notable that the cellular response to nitric oxide-generating agents, as reflected by the induction of HO-1, involves intracellular iron. Induction of HO-1, by virtue of the effect of HO activity on heme, releases iron (22), and this latter effect may increase intracellular iron and thereby exacerbate oxidant stress (36); alternatively, HO-1 may provide a mechanism that exports iron from cells and thus a process that guards against increments in cellular content of iron (11, 33). Perhaps the offsetting effects of these opposing actions of HO-1 on cellular iron homeostasis may underlie the lack of a functional effect on cellular vitality when the activity of induced HO-1 is inhibited by tin protoporphyrin. Other possible explanations may underlie this lack of a functional effect observed with inhibition of HO: the induction of HO-1 may represent an epiphenomenon that simply reflects a biological readout of increments in intracellular iron induced by NO-generating agents; functional effects derived from induced HO-1 do exist but are not necessarily reflected by the LDH release; finally, NO may influence HO activity (18), and this effect may confound the interpretation of studies utilizing inhibitors of HO.
We suggest that our findings are germane to the recent demonstration that nitric oxide is a critical intermediate in models of iron-instigated cell injury (6). Our data, in conjunction with these prior studies (6), raise the possibility that a positive feedback may exist such that the toxicity of either nitric oxide or iron recruits, and relies on, cooperation with the other to achieve the full measure of cytotoxicity. Our findings may also be germane to the mechanism underlying the beneficial effects of iron chelators in models of acute renal injury (31, 35, 38, 41). The efficacy of iron chelators is conventionally ascribed to the interruption of the Habey-Weiss reaction whereby milder oxidants such as superoxide anion and hydrogen peroxide interact under the catalytic effect of iron to generate the highly injurious hydroxyl radical. In light of the current appreciation of the role of nitric oxide in acute tubular injury (10, 14), we speculate that the efficacy of iron chelators in such settings may also reflect the interruption of the recruitment of iron in that pathogenetic chain of events that begins with the copious generation of nitric oxide and ends with acute renal injury.
In summary, we demonstrate the induction of HO-1 in the renal proximal tubular epithelial cells exposed to nitric oxide donors. We present the first demonstration in kidney-derived cells for the involvement of a redox-based mechanism in such expression. We also demonstrate that, in LLC-PK1 cells exposed to nitric oxide donors, chelatable iron is involved in eliciting the HO-1 response observed at lower concentrations of these donors, and in mediating the cytotoxic effects of these donors when present in higher concentrations.
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ACKNOWLEDGEMENTS |
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We gratefully acknowledge the technical expertise of Jill Haggard and the secretarial expertise of Sharon Heppelmann in the preparation of this work.
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FOOTNOTES |
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These studies were supported by National Institutes of Health Grants HL-55552 and RO1 DK-47060 (K.A. Nath).
Address for reprint requests and other correspondence: K. A. Nath, Mayo Clinic, 200 First St. SW, 542 Guggenheim Bldg., Rochester, MN 55905.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 29 December 1999; accepted in final form 25 May 2000.
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