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1 Department of Histopathology, Arginase shares a common substrate, L-arginine, with
nitric oxide synthase (NOS). Both enzymes are active at inflammatory sites. To understand regulation of arginase and its relationship to
nitric oxide (NO) production, we studied effects of
NG-hydroxy-L-arginine
(HOArg) and interleukin-4 (IL-4) on urea and
glomerulonephritis; nitric oxide; L-arginine; N G-hydroxy-L-arginine; adenosine 3',5'-cyclic monophosphate; macrophages; interleukin-4
ARGINASE CATALYZES the conversion of
L-arginine to
L-ornithine and urea. Arginase
activity is found in many tissues that do not express a complete urea
cycle (26, 31). The function of this type of arginase is unknown,
but potential roles in inflammation and immunity are likely, as high
activity is found in stimulated macrophages (20) and inflammatory
lesions (1, 21). As arginase and nitric oxide synthase (NOS) share a
common substrate, the regulation of arginase is linked with nitric
oxide (NO) production, and it has been suggested that the balance of
L-arginine metabolism between these two pathways has important
pathophysi- ological effects (2, 36). The regulation of
L-arginine metabolism in
tissues that possess both arginase and NOS activities is poorly understood. Enhanced arginase products have been shown under conditions of NO inhibition (16), implicating substrate competition between the
arginase and NOS enzymes as one mechanism of control.
Several endogenous compounds already implicated as chemical mediators
in inflammatory reactions have been shown to modulate arginase activity
(3, 39). Most of these compounds also affect NO production. Recently,
an intermediate in the conversion of L-arginine to NO and
L-citrulline,
NG-hydroxy-L-arginine
(HOArg) (54), has been shown to be a potent inhibitor of purified rat
liver arginase (5, 22) and of the arginase activity found in
macrophages (5, 24, 27), endothelial cells (8), gastric mucosal cells
(9), and the insulinoma cell line, RINm5F (19). This compound is
increased in the serum of endotoxin-treated rats (25) and is present in
the serum of healthy humans (35). Conversely, two Th2
lymphocyte-associated cytokines [interleukin-1 and -10 (IL-4 and
IL-10, respectively)] have been shown to increase arginase
activity (18, 36).
Immune-mediated glomerulonephritis is an inflammatory reaction
characterized by induced NOS and arginase activity in nephritic glomeruli (10, 29, 32). Both macrophages and intrinsic glomerular mesangial cells possess arginase and inducible NOS (iNOS) activity and
are possible sources in vivo. We have therefore examined the effects of
potential modulators of arginase activity on nephritic glomeruli, on
mesangial cells and macrophages, and on the isoforms of arginase in
glomeruli, as a means of understanding further the regulation and role
of arginase in glomerulonephritis and its relationship to NOS.
Animals and Chemicals
ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
synthesis by glomeruli during rat
immune glomerulonephritis and compared these with macrophages and
glomerular mesangial cells (MC). In nephritic glomeruli, elicited
macrophages, and MC stimulated with IL-1 and adenosine
3',5'-cyclic monophosphate agonists, increased arginase and
induced NOS activity was found. Urea production was inhibited by HOArg
and increased by IL-4. NO inhibition
[NG-monomethyl-L-arginine
(L-NMMA)] increased
arginase activity in nephritic glomeruli and macrophages but not MC.
synthesis was inhibited by
L-NMMA and IL-4. It was
increased with HOArg under conditions of NO inhibition. In contrast, in
normal glomeruli and basal MC, where there was no induced NO synthesis, IL-4 had no effect on arginase activity, whereas HOArg consistently reduced it in glomeruli only. Type II arginase (Arg II) mRNA was detected in normal glomeruli; nephritic glomeruli expressed both Arg I
and Arg II mRNAs. This is the first demonstration of arginase modulation in glomeruli and MC and of the expression of arginase isoforms in glomeruli. The differential responses to two endogenous compounds generated by inflammation suggest this may be part of coordinated regulation of arginase and inducible NOS in immune injury,
whereby arginase is inhibited during high-output NO production and
stimulated with NO suppression. This, together with control of arginase
and NOS isoforms, may be important in controlling the balance of
inflammatory and repair mechanisms.
INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
Macrophages
Thioglycollate-elicited peritoneal macrophages were cultured as previously described (29). Cells were plated at 106/ml in 16-mm plastic wells (Nunc, Roskilde, Denmark) in 1 ml Dulbecco's modified Eagle's medium (DMEM), supplemented with 4 mM L-glutamine, 1 mg/ml bovine serum albumin (BSA), 100 U/ml penicillin, and 100 µg/ml streptomycin.Mesangial Cells
Mesangial cells were isolated, cultured, and characterized, as previously described (10, 16). Cells were used between passages 7 and 16 in four separate experiments. The results shown here are from one representative experiment. Confluent cultures were incubated in 22-mm plastic wells in 0.5 ml RPMI 1640 supplemented with 1 mg/ml BSA, 100 U/ml penicillin, and 100 µg/ml streptomycin. Mesangial cell protein was measured by the microbicinchoninic acid assay.Glomerulonephritis
Accelerated nephrotoxic nephritis was induced by preimmunization with rabbit immunoglobulin G (IgG) in Freund's complete adjuvant, followed after 7 days by intravenous rabbit anti-rat glomerular basement membrane (GBM) globulin, as previously described (10). Rats were killed at 4 and 7 days after anti-rat GBM globulin.Glomeruli were isolated from kidneys by differential sieving (14) and cultured in 16-mm plastic wells at 2,000/ml in 1 ml DMEM supplemented with 4 mM L-glutamine, 1 mg/ml BSA, 100 U/ml penicillin, and 100 µg/ml streptomycin.
Arginase Activity and
Synthesis
10,000
counts · min
1 · ml1
(final concentration, 0.25 µM). They were cultured in the absence and
presence of NG-monomethyl-L-arginine
(L-NMMA, 300 µM; Cyclops
Biochemical), HOArg (2-200 µM, Calbiochem-Novabiochem), IL-1
(2 nM; NIBSC, Potters Bar, UK), 3-isobutyl-1-methylxanthine (IBMX, 0.5 mM), cholera toxin (1 µg/ml), and IL-4 (8-800 ng/ml).
Recombinant rat IL-4 was produced as a cell culture supernatant from
Chinese hamster ovary (CHO)-K1 cell line transfected with rat IL-4 cDNA
(a gift from Dr. D. Fowell, Medical Research Council Immunology Unit, Oxford, UK) (34). The specific activity of recombinant rat IL-4 was
2,000 units/µg (assessed by upregulation of activity of MHC class II
molecule expression in splenic B lymphocytes) (46). The endotoxin level
was 60 pg/ml in the cell culture supernatant, as assessed by Limulus
amoebocyte lysate assay (lower limit of detection, 50 pg/ml), using a
test kit (Kabi Vitrim, Uxbridge, UK). Cell culture supernatant from the
parent CHO-K1 cell line (endotoxin level, <50 pg/ml) was used as a
negative control.
Arginase activity was measured in cultures by assaying the production
of [14C]urea from
L-[guanido-14C]arginine
in culture supernatants (extracellular arginase activity), as
previously described (29, 49). in culture supernatants from the same wells was measured by the Griess reaction (10).
Intracellular arginase was assayed by radiometric assay performed on cell lysates (29, 48).
Reverse Transcription-Polymerase Chain Reaction
RNA isolation and reverse transcription-polymerase chain reaction (RT-PCR) were performed on nephritic glomeruli (day 4, accelerated nephrotoxic nephritis) and normal glomeruli, as described previously (15). The PCR primers for type I arginase (Arg I) were those used by Buga et al. (8). The primers for type II arginase (Arg II) were designed using the sequence submitted by Iyer and Grody (accession no. U-90887 NID). Arg II primers, which amplify a product of predicted length 612 bp, are 5' GCT-GTG-TCA-CAC-TGG-GAG-GAG-ACC 3' and 5' CTG-CTA-GGC-TGG-CTG-TAG-CCT-TGG 3'. PCR was carried out with an annealing temperature of 58°C for 35 cycles, using two dilutions for each sample, corresponding to 10 and 100 ng of RNA per reaction. The identity of the 612-bp reaction product was confirmed by cleavage into predicted fragment sizes of 142 and 470 bp by the restriction enzyme Dsa I.Statistics
Data are presented as means ± SE for triplicate wells. Analysis of variance with Fisher's protected least significant difference and Student's t-tests was used.| |
RESULTS |
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Effect of HOArg and IL-4 on Peritoneal Macrophages
These compounds had dose-dependent effects on arginase activity (Fig. 1A). HOArg caused greatest inhibition at 200 µM; IL-4 increased activity maximally at 80 ng/ml. In view of these results, the concentrations used in experiments on mesangial cells and glomeruli were 200 µM HOArg and 80 ng/ml IL-4, respectively. HOArg did not change production, but IL-4 decreased production by ~30% at all
concentrations. Control CHO cell media did not affect arginase activity
or production in macrophage,
glomerular, or mesangial cell experiments.
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To examine interaction with the NOS pathway, these experiments were
repeated in the presence of the NOS inhibitor
L-NMMA (Fig. 1B).
L-NMMA reduced basal
generation by 89% and caused a
3.7-fold increase in basal arginase (P < 0.01). The effects on arginase activity by HOArg and IL-4
were exaggerated by L-NMMA (Fig.
1B). With
L-NMMA, HOArg dose dependently
increased generation (20 µM,
P < 0.05; 200 µM,
P < 0.01, compared with no
HOArg), whereas IL-4 significantly reduced generation to a similar degree at
all concentrations (8-800 ng/ml,
P < 0.05, compared with no IL-4)
(Fig. 2).
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Effect of HOArg and IL-4 on Unstimulated Mesangial Cells
Arginase activity was variably affected by HOArg (there was a significant reduction in only 1 of 4 experiments) and unaffected by IL-4 (Fig. 3A). Small but significant amounts of were produced from unstimulated cells in the presence of HOArg (Table
1)
(P < 0.05); this
was not inhibited by
L-NMMA. Under basal conditions
and with IL-4, concentrations were
below the limit of detection.
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Effect of HOArg and IL-4 on Stimulated Mesangial Cells
Stimulation with IL-1. IL-1 increased arginase activity by 60%, compared with unstimulated cells (P < 0.05) (Fig. 3B). HOArg had no significant effect; however, IL-4 blunted the stimulatory effect of IL-1 (P < 0.05 vs. no IL-1). IL-1 induced production (Table 1)
(P < 0.01). HOArg caused a small but
significant drop in production
(P < 0.01), and IL-4 almost
abolished production
(P < 0.01).
Stimulation with adenosine 3',5'-cyclic
monophosphate agonists cholera toxin and IBMX.
Adenosine 3',5'-cyclic monophosphate (cAMP) agonists
increased arginase activity by 79%, compared with unstimulated cells
(P < 0.01) (Fig.
3C). HOArg had no effect, whereas
IL-4 augmented this activity by an additional 38%
(P < 0.01). cAMP agonists alone did
not induce production. HOArg
caused a small but significant increase in
(P < 0.05); IL-4 had no effect
(Table 1).
Stimulation with IL-1 and cAMP
agonists. cAMP agonists in combination with IL-1 were
used to stimulate maximal production. This doubled arginase activity, compared with unstimulated cells (P < 0.01) (Fig.
3D). HOArg significantly inhibited
(P < 0.01) and IL-4 increased
arginase activity (P < 0.05). This
combination stimulated greater
production than IL-1 alone (P < 0.01). HOArg slightly inhibited (P < 0.05) and IL-4 strongly inhibited
production (P < 0.01) (Table 1).
NO inhibition with L-NMMA did not alter arginase activity in either unstimulated or stimulated mesangial cells (data not shown).
Effect of IL-4 on intracellular arginase activity in
mesangial cells. Mesangial cells were incubated with or
without the combination of IL-1 and cAMP agonists in the presence or
absence of IL-4. IL-4 caused a 21% increase in intracellular arginase
activity (stimulated cells + IL-4 vs. basal,
P < 0.05; IL-4 increased arginase activity in basal cells but this did not reach statistical
significance).
Effect of HOArg and IL-4 on Glomeruli
Preimmunization with subsequent administration of anti-GBM globulin induced a proliferative glomerulonephritis with macrophage infiltration. As we previously reported (29), there was arginase activity in normal glomeruli, which was significantly increased in nephritic glomeruli at day 4 (P < 0.05) (Fig. 4). HOArg inhibited arginase activity in both normal and nephritic glomeruli (Fig. 4A). In contrast, IL-4 significantly increased the activity but only in nephritic glomeruli. Nephritic, but not normal, glomeruli generated significant (Table
2) (P < 0.01). This was markedly reduced by IL-4
(P < 0.05); HOArg had no effect. In
normal glomeruli, was higher in
the presence of HOArg (P < 0.05).
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NOS inhibition with L-NMMA did
not alter arginase activity in normal glomeruli (Fig.
4B). In nephritic glomeruli under
basal conditions and with HOArg,
L-NMMA increased arginase
activity (P < 0.05, basal and with
HOArg). The IL-4-enhanced arginase activity was no greater in the
presence of L-NMMA.
L-NMMA inhibited
generation by nephritic glomeruli
under basal conditions (P < 0.01),
with HOArg (P < 0.01) and with IL-4
(P < 0.05) (Table 2).
The responses to IL-4, HOArg, and L-NMMA were identical in day 7 glomeruli (results not shown).
Expression of Arginase Isoforms Arg I and II in Glomeruli
Arg II was detected in both normal and nephritic glomeruli; Arg I was only detected in nephritic glomeruli (Fig. 5).
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DISCUSSION |
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Abstract
Introduction
Materials & Methods
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Discussion
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We have previously reported that nephritic glomeruli show activity in
two major pathways of L-arginine
metabolism, iNOS-dependent NO production (10-12, 17) and urea and
ornithine synthesis via arginase (29). The role of arginine metabolites
in glomerulonephritis is unknown. NO could promote injury through its
cytotoxic effects, modulate glomerular hemodynamics, or have
anti-inflammatory effects by inhibiting leukocyte migration and
neutralization of other reactive radical species (13). It has been
suggested that arginase and its products at inflammatory sites produce
an environment favorable for healing fibroblast replication and
collagen synthesis (51). To understand the significance of arginase
activity in immune inflammation and its interaction with NO synthesis,
we have now examined the effects of two compounds, HOArg and IL-4, endogenous compounds increased in vivo in inflammation (25, 30, 41) and
recently shown to modulate arginase activity (5, 8, 9, 18, 19, 22, 24,
27, 36). HOArg is an intermediate in the conversion of
L-arginine to NO; it
accumulates in the culture medium of cells synthesizing NO (8). IL-4 is
a lymphocyte-derived cytokine synthesized mainly by Th2 cells; it has
been reported to increase arginase activity in macrophages (18, 36) and also inhibits macrophage iNOS expression (33, 42). We measured arginase
activity by measuring the synthesis of urea from
L-arginine in culture and NOS
activity by measuring synthesis.
The assay of these end products will detect changes in the amounts of
the respective enzymes, changes in their activity due to the presence
of inhibitors, or changes in the quantity of
L-arginine substrate available
to the enzyme.
HOArg and IL-4 modulated glomerular arginase activity and
production. HOArg inhibited
arginase activity in both normal and nephritic glomeruli, and IL-4
enhanced the activity in nephritic glomeruli. This action of IL-4 could
be highly relevant in vivo, for it has recently been detected in nephritic glomeruli (30, 41). Whether there is significant production
of HOArg in glomeruli is unknown. NO inhibition increased basal
arginase activity in nephritic glomeruli, as we have previously reported (16). One explanation for this effect is competition between
the two pathways for substrate and reduction of NO synthesis, allowing
more L-arginine to enter the
arginase pathway. The Michaelis constant
(Km)
for arginine as a substrate for macrophage arginase is relatively high
(4-9 mM) (7), consistent with this. Alternatively, when NOS is
active, HOArg, produced as an intermediate, inhibits arginase activity,
and this inhibition is reduced when the NOS pathway is blocked by
L-NMMA. HOArg and IL-4 were
still able to modulate arginase activity when NO synthesis was
inhibited by L-NMMA,
showing that the stimulatory effect of IL-4 on arginase activity is not simply due to inhibition of NO synthesis. The glomerular nitrite synthesis in nephritic glomeruli was inhibited by
IL-4. Normal glomeruli do not produce nitrite ex vivo; addition of
HOArg led to detectable levels of nitrite, not inhibitable by
L-NMMA. This suggests that HOArg
is either able to enter the synthetic pathway downstream of the point
where L-NMMA exerts its inhibitory effect on NOS
or that there is an alternative pathway by which HOArg is converted to
, possibly catalyzed by
P-450, as suggested by other studies
(6, 47).
We then examined whether macrophages and mesangial cells, two cell
types central to the inflammatory reaction in acute glomerulonephritis, behaved in the same way as nephritic glomeruli or whether differences in responses might reveal a dominant source of arginase in
glomerulonephritis. Arginase modulation has previously been studied in
several macrophage cell types, but this is the first report examining
the mesangial cell, an intrinsic glomerular cell closely related to
vascular smooth muscle. In both cell types, HOArg and IL-4 modulated
arginase activity. In macrophages, HOArg reduced and IL-4
increased arginase activity, consistent with previous reports for
alveolar (24) and bone marrow-derived (18, 36) macrophages. NO
inhibition increased arginase activity, as we (16) and others (28) have previously shown. As for glomeruli, this may reflect either competition for substrate or reduction in synthesis of HOArg as an intermediate. IL-4 reduced synthesis, consistent
with previous reports that it reduces iNOS activity in stimulated
macrophages (4, 33, 42). When
synthesis was inhibited by
L-NMMA, addition of HOArg
increased nitrite as seen with glomeruli.
In glomeruli and cultured mesangial cells, there is constitutive arginase activity, as we have previously reported (29). When glomeruli are stimulated by immune complex injury or mesangial cells by IL-1 or cAMP agonists, we find there is a significant increase in arginase activity. This suggests that, in vivo, under conditions of cytokine or other inflammatory stimulation, intrinsic glomerular mesangial cells could be a major source of L-ornithine synthesis. IL-4 further enhanced the arginase activity of mesangial cells stimulated with IL-1 and cAMP agonists, and this was due to increased intracellular arginase. IL-4 did not affect the arginase activity of unstimulated mesangial cells. This may explain why IL-4 did not affect the arginase activity of normal glomeruli but enhanced it in nephritic glomeruli. IL-4 reduced IL-1-stimulated arginase activity (37). As IL-4 inhibits IL-1-induced prostaglandin E2 (PGE2) synthesis in mesangial cells and PGE2 stimulates arginase activity in macrophages (18), this effect could be through loss of PGE2. An inhibitory effect of IL-4 on IL-1-stimulated mesangial cell collagen synthesis has also been reported (38). We were unable to show a consistent inhibitory effect of HOArg on basal arginase activity in mesangial cells. This could indicate that the basal expression is from a form of arginase less susceptible to HOArg inhibition or may be because HOArg is not efficiently transported into resting mesangial cells.
Two distinct and nonhomologous arginase genes exist in mammals, and their products have been termed arginase I and arginase II (53). Arginase I is found predominantly in the liver but is also induced in rat peritoneal macrophages, in response to lipopolysaccharide (LPS) stimulation (52). Arginase II is present in extrahepatic tissues, including kidney, small intestine, and lactating mammary gland. The gene for arginase II has recently been cloned in humans (56) and rats (23). This isoform may also be induced by appropriate stimuli. In a murine macrophage cell line, LPS stimulation led to increased arginase activity, and immunoprecipitation experiments showed that this was due to an increase in arginase II levels (57). In the same cells, cAMP agonists have been shown to increase levels of mRNA for arginase II (23). Similarly, in rat aortic endothelial cells, there was constitutive expression of arginase I and induction of arginase II by LPS (8). We have now examined the expression of the mRNA for these two isoforms in normal and inflamed glomeruli. We found that, in normal glomeruli, only arginase II was detectable, whereas, in nephritic glomeruli, both isoforms were expressed. These are the first studies showing differential expression of arginase isoforms at an inflammatory site. Our results indicate that, in normal glomeruli, there is constitutive expression of arginase II by an intrinsic glomerular cell, most likely the mesangial cell. The expression of arginase I during nephritis may either reflect induction in intrinsic glomerular cells or an influx of activated macrophages expressing this isoform.
Glomerular mesangial cells synthesize NO via the high-output iNOS
enzyme (44). synthesis induced in mesangial cells by IL-1, or IL-1 and cAMP agonists was
markedly inhibited by IL-4, as has been previously shown in macrophages (4) and human mesangial cells (50). This is the first demonstration of
a similar inhibitory effect in rat mesangial cells. Other cytokines, such as transforming growth factor- (TGF-), platelet-derived growth factor (PDGF), and IL-13, have been shown to reduce mesangial cell NO synthesis (43, 45, 50). Unlike macrophages and nephritic glomeruli, inhibition of mesangial cell NO synthesis had no effect on
arginase activity, even with the high
levels synthesized by IL-1- and
cAMP agonist-stimulated cells. One possible explanation is
compartmentalization of arginase and NO synthesis in mesangial cells;
another is that the cultures of mesangial cells are heterogeneous, with
some cells synthesizing NO and others synthesizing arginase. Recent
data have shown that only a proportion of mesangial cells in culture
can be stimulated to synthesize iNOS (40).
These experiments have not determined the source of arginase activity in nephritic glomeruli, since the response to HOArg and IL-4 were similar to nephritic glomeruli in both in vitro cell types. It is likely that both macrophages and mesangial cells contribute to arginase activity in the inflamed glomerulus, although, quantitatively, mesangial cells are likely to be the main source of the arginase activity measured in nephritic glomeruli (16).
From these results, we suggest the following hypothesis for the activity of these pathways in the glomerulus in vivo. In the normal glomerulus, there is low basal arginase activity, due to the presence of arginase II in mesangial cells, but the iNOS pathway is inactive. The function of the arginase generated here may be to sustain normal protein synthesis for glomerular cells and extracellular matrix. In nephritic glomeruli, there is increased arginase activity, due to induction of arginase I and possibly also increased activity of arginase II. The relative activities of the two pathways of arginine metabolism will be modulated by inflammatory cytokines, the presence of inflammatory cells, the levels of available arginine, and accumulating HOArg. Our previous temporal analysis (16) showed high NO in the earliest phase of injury, followed, after several days, by increased arginase, and this pattern is also associated with wound healing (2). The HOArg produced from the iNOS pathway may inhibit arginase, ensuring arginine availability for high-output NO production, as suggested by Buga et al. (8). IL-4 is potentially a major mediator of the balance between the two pathways, since it is able both to inhibit iNOS activity in mesangial cells and macrophages and to stimulate arginase activity by enhancing the synthesis of arginase II. IL-4 mRNA and protein have been detected in glomeruli in experimental and human glomerulonephritis, and its administration has anti-inflammatory effects in acute glomerulonephritis (55). Its effect on the pathways of L-arginine metabolism would be to reduce NO synthesis and promote the synthesis of urea and ornithine. Ornithine is able to act as a substrate for the synthesis of polyamines necessary for cell proliferation and proline needed for collagen synthesis. Thus IL-4 may play a major role in the switch from high NO during inflammation to low NO and increased ornithine synthesis during repair and regeneration.
These studies suggest that endogenous HOArg and IL-4 may be modulators of L-arginine metabolism in glomerular inflammation and important in controlling the balance of inflammatory and repair mechanisms. They also identify, for the first time, expression of arginase isoforms in the normal and nephritic glomerulus.
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ACKNOWLEDGEMENTS |
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This work was supported by the Wellcome Trust United Kingdom. F. W. K. Tam is a National Kidney Research Fund Senior Research Fellow.
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FOOTNOTES |
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Address for reprint requests: V. Cattell, Dept. Histopathology, Imperial College School of Medicine at St. Mary's, Norfolk Place, London W2 1PG, UK.
Received 3 July 1997; accepted in final form 13 November 1997.
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Abstract
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Materials & Methods
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Discussion
References
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