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Division of Nephrology-Hypertension and Pathology, University of California, Department of Medicine, San Diego, and VA San Diego Healthcare System, La Jolla, California.
Correspondence to Dr. Roland C. Blantz, Professor and Head, Division of Nephrology-Hypertension, UCSD & VA Medical Center, 3350 La Jolla Village Drive, San Diego, CA 92161. Phone: 619-552-7528; Fax: 619-552-7549; E-mail: rblantz{at}ucsd.edu
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A third arginine metabolic pathway, the conversion of arginine to agmatine by arginine decarboxylase (ADC), has recently been described in mammals (7). ADC activity is prevalent in the kidney, liver, and brain. Similarly, agmatine is present in the plasma and has been observed in multiple tissues and cell types (8,9,10). Agmatine exerts functional effects within the kidney, elevating single nephron filtration rate (SNGFR) via vasodilatation by constitutive NOS (cNOS) and ryanodine channel-dependent mechanisms (10,11). Agmatine also suppresses NO generation by iNOS in vitro (12,13; Satriano et al., submitted). Studies have recently shown that agmatine inhibits ODC activity and polyamine transport by an ODC-antizyme—dependent mechanism (14). These data suggest that agmatine could exert important effects on both NO production and cell proliferation in inflammatory conditions.
It is widely recognized that NO production is increased after induction of accelerated nephrotoxic-serum GN, active Heymann GN, in situ immune complex GN, and anti—Thy-1 antibody—induced GN (Thy-1 nephritis) (4,5,15). Thy-1 nephritis is a model of acute mesangial proliferative GN in rats that is characterized by early mesangial cell (MC) injury, followed by MC proliferation (16,17). Augmentation of arginase activity and ODC and OAT expression in the repair phase result in cellular proliferation and extracellular matrix production in this model (3,18,19,20). Therefore, we chose the Thy-1 nephritis model to investigate the in vivo effects of agmatine on injury and repair.
Our results provide the first evidence that agmatine can limit MC proliferation and improve renal function in experimental mesangial proliferative GN.
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Materials and Methods |
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Awake Animal Studies of GFR and Urinary Protein Excretion
To measure 3H-inulin clearance, cannulated rats were prepared as
previously described
(21,22).
In brief, animals were anesthetized and catheters were placed in the left
femoral artery, vein, and bladder. After a 3-d recovery from the cannulation
procedure, rats were divided into three experimental groups:
Thy-1—treated rats, Thy-1 + Ag—treated rats, and
agmatine-only—treated rats (n = 6 per group). Three
measurements of GFR in each animal were performed at days 0, 1, 4, and 7. For
determination of urinary protein excretion, a 24-h urine collection was
filtered, precipitated by 10% trichloroacetic acid (TCA), collected by
centrifugation, and measured by the method of Lowry et al.
(23).
Renal Morphology
Kidney tissue was fixed in 10% buffered formalin and embedded in paraffin.
The paraffin-embedded tissues were sectioned and stained with periodic acid
Schiff. Three observers, blinded to the treatments, semiquantitatively graded
glomerular injury, extracellular matrix accumulation, and cellular
proliferation of each quadrant in 30 glomeruli per kidney on a scale from 0 to
4 using the following scales. Injury score: 0 = absence of mesangiolysis; 1 =
mesangial area (MA) showing slight lucency (0 to 25% disruption of MC); 2 = MA
showing moderate lucency (25 to 50% disruption of MC) with preservation of the
underlying glomerular tuft architecture; 3 = MA showing severe lucency (50 to
75%) with degeneration and disruption of MC; 4 = MA showing complete
dissolution (75 to 100%) with disappearance of MC, usually in association with
microaneurysm formation. Matrix score: 0 = decrease in mesangial matrix (MM);
1 = no increase in MM; 2 = slight increase in MM; 3 = moderate increase in MM;
4 = almost confluent appearance of MM. Each score reflects changes in the
extent rather than in the intensity of MM staining. Proliferation score: 0 =
no nests of proliferating cells (PC); 1 = normal number of PC; 2 = slight
increase in PC; 3 = moderate increase in PC; 4 = substantial increase in PC.
To compare the glomerular cell number quantitatively, we individually counted
nuclei and polymorphonuclear leukocytes (PMN) in 30 glomeruli from each
rat.
Immunohistochemical Staining for Proliferating Cell Nuclear
Antigen
Tissue sections in metharcarn solution were incubated overnight at 4°C
with 19A2, a murine IgM monoclonal antibody against human proliferating cell
nuclear antigen (PCNA; Coulter cytometry), followed by a peroxidase-conjugated
rat anti-mouse IgM (Zymed Laboratory, San Francisco, CA). PCNA is an acidic
nuclear protein that increases from the late G1 to S phases of the cell cycle,
followed by a decrease in G2/M. Black nuclear staining was detected using
diaminobenzidine (Dakopatts, Glostrup, Denmark), and slides were
counterstained with methyl green. The negative control consisted of
substitution of the primary antibody with a normal mouse IgM monoclonal
antibody (Dakopatts). To determine the number of proliferating cells in
individual animals, a blinded observer evaluated 30 to 40 glomerular profiles
containing more than 20 discrete capillary segments, and positive staining was
defined as black nuclear staining.
Immunofluorescence Staining for Macrophage/Monocytes and
Anti—Thy-1 Antibody
To assess whether agmatine reduces anti—Thy-1 antibody binding to
glomeruli, thereby causing an alteration in the extent of injury, we performed
immunofluorescence studies. Anti—Thy-1 antibody has been shown to bind
maximally to glomeruli in the first 24 h after administration
(16). Therefore, we assessed
the amount of Thy-1 antibody binding to mesangial cells 24 h after disease
induction. The kidney cortices were snap-frozen in OCT compound, sectioned at
3 µm, fixed with acetone for 7 min, washed twice in phosphate-buffered
saline (PBS), and then incubated with goat FITC-labeled anti-mouse IgG (Sigma
Chemical Co.) to detect the binding of anti—Thy-1 antibody to the MC
surface. The sections were also incubated with anti-ED1, a mouse monoclonal
FITC-labeled anti-rat monocyte/macrophage (Serotec, Oxford, England) antibody.
The glomerular ED-1 positive cells were counted in 30 glomeruli from each rat.
The intensity of binding of anti—Thy-1 antibody was graded from 0 to 4
+.
ODC Activity Assay
The activity of ODC was determined by measuring the conversion of
L-(1-14C)-ornithine to 14CO2. After the
kidneys were removed, sections of the cortex were immediately suspended in ODC
reaction buffer (10 mM Tris [pH 7.4], 2.5 mM dithiothreitol, 0.3 mM
pyridoxal-5-phosphate, 0.1 mM ethylenediaminetetraacetate) and homogenized for
10 s. The homogenate was centrifuged at 30,000 x g for 40 min,
and the supernatants were assayed for ODC activity as described
(14). Briefly, large bore
tubes capped with rubber stoppers fitted with metabolic wells (Kontes,
Vineland, NJ) containing trapping agent (Solvable, Packard Instruments,
Meriden, CT) were used to incubate the supernatants at 37°C for 1 h in the
presence of 0.1 µCi (1-14C)-ornithine (Dupont-NEN, Boston, MA).
TCA was added to terminate the reaction, and after an additional 1 h,
equilibration ß scintillation counting was performed. Aliquots of the
supernatants in the Thy-1 group were also incubated for 1 h with 1 mM
L-N6-(1-iminoethyl)-lysine, (L-NIL; Alexis Biochemicals, San Diego,
CA), a specific iNOS inhibitor, to determine in vitro whether changes
in NO could alter ODC activity.
Isolation and Incubation of Glomeruli
After the kidneys were removed, they were decapsulated and bisected and the
cortex was carefully dissected free. Cortices were gently pressed through a
180- then a 106-µM stainless steel sieve. The resulting material was
suspended in Krebs buffer at 4°C and gassed with 95% O2/5%
CO2. The buffer consisted of 125 mM NaCl, 5 mM KCl, 1 mM
CaCl2, 0.75 mM NaH2PO4, 0.75 mM
Na2HPO4, 0.5 mM MgCl2, 10 mM glucose, and 15
mM NaHCO3. Then the suspension was passed through a 75-µM sieve.
The glomeruli trapped on the sieve were washed and pelleted by centrifugation
at 3000 RPM for 1 min. After graded sieving, glomeruli were suspended in
Dulbecco's modified Eagle's medium (DMEM) without phenol red for the cell
proliferation and nitrite assays. The remaining pellet was resuspended in
Krebs buffer, aliquoted, and used for the cGMP assay.
Glomerular Cell Proliferation Assay
The proliferation assay was performed using the method described by
Ketteler et al. (3).
After graded sieving, cell strainers were placed in a six-well plate and
glomeruli resuspended in DMEM (3 ml/well) were pipetted onto the cell
strainers. 3H-thymidine (1 µCi/well) was added to the cell
strainers and incubated for 24 h. The cell strainers were then removed from
the six-well plate, rinsed with cold PBS, placed into the six-well plate
again, and washed three times for 10 min with 2 ml of 5% TCA per well. Then 2
ml of 0.5 M NaOH/0.1% sodium dodecyl sulfate was added to each well, and the
plates were agitated at 100 RPM for 30 min. Samples were neutralized with 0.6
mol/L HCl, and radioactivity in 500-µl aliquots was determined.
Nitrite Assay
Nitrite was measured using the Griess reaction
(24). After the isolated
glomeruli were incubated for 24 h in DMEM in a 24-well plate, the supernatants
were harvested and centrifuged at 14,000 x g for 5 min to
remove the glomeruli. Total nitrite was then measured at 550 nm in an
autoplate reader. Isolated glomeruli in the Thy-1 group were also incubated
for 24 h in DMEM with 100 µM L-NIL or 100 µM agmatine to assess in
vitro their inhibitory effects on NO production. Assays were done in
triplicate.
cGMP Assay
We measured cGMP, a second messenger of NO, to estimate indirectly
glomerular NO activity. The aliquots (50 µl/tube) of glomeruli resuspended
in Krebs buffer were incubated at 37°C for 10 min and then were added to
50 µl of Krebs buffer with 1 mM 3-isobutyl-1-methyl-xanthine (Sigma
Chemical Co.) to inhibit degradation of cGMP. The aliquots were incubated for
an additional 4 min, then 100 µl of 10% TCA was added to terminate the
reaction. The aliquots were centrifuged at 3000 RPM at 4°C for 20 min. The
pellet was extracted in 2 N NaOH and used for protein determination. The
aliquots in the Thy-1 group were also preincubated for 10 min with 10 mM
sodium nitroprusside (SNP; Sigma Chemical Co.) to assess whether a direct NO
donor could elicit an increase in cGMP levels. The supernatants obtained from
the aliquots were ether extracted and lyophilized, and the remaining pellets
were used for RIA determination of cGMP with an RIA kit (Dupont-NEN).
Statistical Analyses
All data are expressed as the mean ± SEM. Histologic data were
averaged across three raters, across 30 glomeruli within each quadrant, and
across quadrants to yield mean injury, proliferation, and matrix scores for
each animal. The data were then evaluated with a two-way ANOVA and post
hoc Tukey tests. GFR was measured repeatedly in each animal, and the data
were analyzed by repeated measures ANOVA. The remainder of the data were
analyzed by two-way ANOVA followed by Tukey test for multiple group
comparisons.
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Results |
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Histologic Studies
The glomeruli on day 1, as assessed by light microscopy, showed signs of
injury with diminished cell numbers in both the Thy-1 and Thy-1 + Ag groups as
compared with the controls (Figure 2, B and
E, versus Figure
2A, respectively), and the histologic appearance of the two
Thy-1—treated groups was similar. Our evaluation showed no significant
difference in the injury score in the two groups at day 1, but the sample size
may have limited the power to detect a small difference
(Figure 3). However, other
studies support that there was an equivalent degree of injury in both
treatment groups. First, immunofluorescence studies revealed no qualitative
difference in distribution or intensity of the staining of anti—Thy-1
antibody or in the number of ED-1—positive cells between the Thy-1 and
Thy-1 + Ag groups (Table 1).
Furthermore, there was no difference in the total number of nuclei and PMN on
day 1 (Table 1), and there was
no alteration in the degree of proteinuria (167 ± 32 versus
158 ± 28, Thy-1 versus Thy-1 + Ag), suggesting that agmatine
did not influence the initial degree of injury. By day 4, the glomeruli in the
Thy-1 group were characterized by focal and segmental hypercellularity in the
mesangium with occasional disintegration of the mesangial architecture
(Figure 2C). This was followed
at day 7 by a marked increase in extracellular matrix and MC proliferation
(Figure 2D). In contrast, there
was a decrease in the proliferation and matrix scores at day 4, which become
statistically significant at day 7 in the Thy-1 + Ag group (Figures
2, F and G, and
3). Reductions both in the
number of cells that stained for PCNA
(Figure 4) and in
3H-thymidine incorporation
(Figure 5A) in the Thy-1 + Ag
group as compared with the Thy-1 group provide additional evidence that
agmatine treatment diminished cellular proliferation at days 4 and 7.
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Administration of Agmatine after Induction of Thy-1 Nephritis
Agmatine was also administered 24 h after induction of Thy-1 nephritis to
provide evidence that the alterations in proliferation and matrix accumulation
induced by agmatine were not secondary to changes in the initial degree of
injury. The matrix and proliferation scores again were reduced in the
agmatine-treated group, and ODC activity was reduced by almost 50% by agmatine
treatment (Table 2). These
findings suggest that agmatine's ability to reduce cellular proliferation and
matrix accumulation in this model is not due to a reduced degree of
injury.
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Glomerular Cell Proliferation and ODC Activity
Proliferation in isolated glomeruli was measured by 3H-thymidine
incorporation. Glomerular cell proliferation in the Thy-1 group was
significantly increased on day 4 (3403 ± 183 versus 2424
± 54, Thy-1 versus Control, P < 0.01), and the
Thy-1 + Ag group exhibited significantly reduced cellular proliferation on
days 1, 4, and 7 as compared with the Thy-1 group (2130 ± 52, 2630
± 175, 2197 ± 57, P < 0.05 versus Thy-1,
Figure 5A). The group that was
treated only with agmatine served as a time control on days 1 through 7. We
also measured ODC activity, the rate-limiting polyamine biosynthetic enzyme,
as another index of the effect of agmatine on MC proliferation. ODC activity
in the Thy-1 group achieved significant peak levels on day 1 (25559 ±
2243 versus 1168 ± 252 cpm/mg protein, day 1 versus
Control, P < 0.01) and was maintained above control levels on days
4 and 7 (22000 ± 2211, 16719 ± 1923, P < 0.01). ODC
activity in the Thy-1 + Ag group was also markedly elevated above the control
during the experimental period (11430 ± 527, 11536 ± 726, 2151
± 213, P < 0.01 versus Control) but was
significantly lower than that of the Thy-1 group (P < 0.05
versus Thy-1, Figure
5B) on all days evaluated. Addition of L-NIL to the supernatants
from the Thy-1 group did not cause a significant difference in ODC activity
during the experimental period (data not shown). This suggests that reductions
in NO were not responsible for alterations in ODC activity.
Nitrite Production in Isolated Glomeruli
Nitrite production in glomeruli isolated from rats in the Thy-1 group
achieved significant peak levels on day 1 (172.9 ± 22.2 versus
6.5 ± 0.9 nmol/mg protein, Thy-1 versus Control, P
< 0.01), remained high on day 4 (73.1 ± 9.7, P < 0.01),
and declined by day 7 (17 ± 1.4, not significant). Nitrite production
in the Thy-1 + Ag group was also elevated above control, but these levels were
only 77% and 59% of those measured in the Thy-1 group on days 1 and 4,
respectively (Figure 6). Addition of L-NIL to glomeruli isolated from the Thy-1—treated rats
greatly reduced NO products to 17% on day 1 and 11% on day 4 (data not shown),
suggesting that the increase in NO production was due to iNOS activity. When
compared with the L-NIL effects, in vitro addition of agmatine
demonstrated only weak inhibitory effects on NO production (79% at day 1 and
76% at day 4 of Thy-1 levels).
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Intracellular Glomerular cGMP Concentration
cGMP, the second messenger of NO, was measured to assess indirectly the
alterations in NO production. Paradoxically, despite the high levels of NO
measured in the Thy-1—treated groups at days 1 and 4, there was no
physiologically significant increase in cGMP as compared with the controls
(agmatine-only—treated group, Figure
7). To examine the response of guanylate cyclase to an NO donor,
SNP was added to glomeruli isolated from the Thy-1 group. In parallel with the
in vivo data, there was no significant increase in cGMP levels after
administration of SNP on days 1 and 4, but this responsiveness was restored at
day 7 (data not shown). Because other enzyme systems such as iNOS and ODC were
intact and upregulated on day 1 of the Thy-1 GN model, it is likely that
despite elevated NO, the decline in cGMP levels is more likely caused by a
reduction in GTP availability or altered redox environment due to mesangial
injury. By day 7 in both the Thy-1 and Thy-1 + Ag groups, there was a
significant increase in cGMP levels as compared with the control group
(P < 0.01), suggesting restoration of guanylate cyclase activity
or GTP levels during the MC proliferative phase.
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Discussion |
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Thy-1 nephritis has an early injury phase characterized functionally and histologically by a reduction in GFR and by mesangiolysis. This is followed by the repair phase in which there is extensive cellular proliferation and matrix accumulation. In this study, administration of agmatine significantly attenuated the decline in GFR without appreciably altering the initial degree of injury. During the repair phase, which is associated with markedly elevated ODC activity, agmatine substantially reduced ODC activity in the Thy-1—treated rats. Similarly, there was a decrease in cellular proliferation and matrix accumulation in the rats treated with agmatine, and these alterations did not seem to be attributable to reduced binding of anti—Thy-1 antibody to MC or to reduced glomerular infiltration by monocytes/macrophages.
The first phase of Thy-1 nephritis lasts up to 1 d after administration of the Thy-1 antibody. Glomerular injury is partially due to the effects of high-output NO generation by iNOS, and the expression of this inducible enzyme has been localized to infiltrating macrophages and polymorphonuclear leukocytes rather than intrinsic glomerular cells (3,5,19). This suggests that the arginine/NO pathway is involved in the pathogenesis of tissue injury. In fact, inhibition of NO synthesis with NG-monomethyl-D-arginine (L-NMMA), a nonspecific NOS inhibitor, has been reported to reduce MC lysis significantly (28).
Agmatine has been shown in vitro to inhibit iNOS, resulting in decreased NO production (12,13; Satriano et al., submitted). However, in this study, there was only a 23% and 41% decline in NO production in the agmatine-treated Thy-1 rats as compared with untreated Thy-1 rats on days 1 and 4. The lack of a significant alteration in the degree of injury may have been due to this limited inhibition of NO production. However, it is possible that the levels of NO measured in this study may have underestimated in vivo levels, because they were performed ex vivo on isolated glomeruli, incubated for 24 h in DMEM without exogenous agmatine.
In the present study, agmatine treatment significantly reversed the decline in GFR in the Thy-1—treated rats (Figure 1) and the reduction in NO production by agmatine treatment on day 1 was probably not sufficient to explain the preservation of GFR observed (Figure 6). Similarly, the agmatine-mediated improvement in GFR cannot be attributed to a difference in initial injury (Figures 2 and 3) or to a reduction in the recruitment of macrophage/monocytes into glomeruli (Table 1) on day 1. It is interesting that the control rats treated with 50 mg/kg of agmatine intraperitoneally did not exhibit an increase in GFR, which seems at odds with our earlier findings that agmatine increases SNGFR (10). The most likely reason for this finding is that the doses of agmatine achieved intrarenally in this study probably were much lower than the 1 µM urinary space concentrations achieved in the previous microperfusion experiments.
We previously demonstrated that microperfusion of agmatine into the renal interstitium or into the urinary spaces of surface nephrons produces an increase in nephron filtration rate, which is largely mediated by an increase in plasma flow caused by vasodilatation (10). These effects of agmatine were prevented by coadministration of a nonselective NOS blocker, indicating that the vasodilatation partially depends on constitutive NOS (11). Other groups have shown that agmatine may function as an endothelial NOS (eNOS) agonist (29). In the Thy-1 nephritis model, we recently demonstrated that pretreatment with L-NIL, a specific iNOS inhibitor, did not prevent a reduction in GFR at day 1, whereas the nonselective inhibitor L-NAME further decreased GFR, suggesting that activation of cNOS may preserve GFR (Ishizuka et al., unpublished observations). Likewise, Goto et al. (19) reported an increase in eNOS activity in the early phase of this model. Recently, we demonstrated that production of high levels of NO in the lipopolysaccharide (LPS) model can downregulate the eNOS enzymes (isoform switching) (30). Pretreatment with agmatine can prevent the reduction in BP and GFR in the LPS model (Satriano et al., submitted). These data suggest that agmatine preserves eNOS effects in pathologies associated with high NO production, such as GN.
In addition to its effects on NOS isoforms, agmatine has been shown to alter polyamine synthetic pathways, important in cellular proliferation. Increased ODC expression has been described in animal models of diabetes and LPS-induced inflammation (31,32,33). Agmatine administration results in the inhibition of ODC activity and the concurrent inhibition of polyamine transport by promoting translation of the ODC antizyme (14). The resulting depletion of intracellular polyamine levels by agmatine administration suppresses proliferation (14).
The data from the present studies demonstrate that ODC activity is markedly increased as early as day 1 after anti—Thy-1 antibody administration, and these high levels of activity persisted during the later cell proliferation phases (Figure 5B). Agmatine treatment in Thy-1 rats significantly attenuated the increase in ODC activity and resulted in reduced glomerular cell proliferation (Figures 3 and 5B). The histologic observation of a decrease in cellular proliferation was supported by a decrease in both the number of PCNA-positive staining cells and in glomerular 3H-thymidine incorporation at days 4 and 7 (Figures 4 and 5A). On the basis of these data, it is likely that agmatine reduces MC proliferation via suppression of ODC.
Agmatine therapy clearly reduced cell proliferation by day 7 in Thy-1 nephritis. We have argued that this reduction in cellular proliferation is a direct effect of agmatine therapy. However, the amelioration of cell proliferation also could have derived from lesser cell injury on day 1 as a consequence of agmatine administration. Therefore, we made considerable efforts to assess this issue and did not discern any difference in initial glomerular injury between untreated and agmatine-treated Thy-1 nephritis rats, using histologic scoring, evaluation of the number of nuclei, infiltrating PMN and macrophages, and extent of binding of anti—Thy-1 antibody. ODC levels were reduced by agmatine therapy on day 1, but we interpret these findings as early indicators of cell proliferation rather than as indices of cellular injury. Nevertheless, we acknowledge that small differences in initial injury may be difficult to detect despite our objective efforts. Because of this possibility, we designed other studies that obviate the possibility of an agmatine effect on initial MC injury. In a second group of rats, we began agmatine therapy 24 h after administration of the Thy-1 antibody, thereby guaranteeing that the initial injury was equivalent in both untreated and agmatine-treated rats. When these results are evaluated (Table 2), we observed reductions in parameters of cell proliferation including histologic evaluation and ODC activity in the rats that received agmatine beginning 24 h after the initial immune insult. We conclude from these separate studies that agmatine exerts a significant antiproliferative effect that is independent of any influence on initial glomerular injury.
Herein we provide the first in vivo results of the effects of agmatine on cellular injury and repair. Agmatine influences MC proliferation and the accumulation of extracellular matrix in the Thy-1 nephritis rats, when given before and after disease induction. Although this model was not performed to assess effects of agmatine on different NOS isoforms, further studies should be undertaken to examine how the agmatine pathway affects the balance of NOS isoform activities in GN and regulates NO and polyamine synthesis to mediate the antiproliferative effects.
The present study demonstrated that agmatine administration can improve GFR and, thus, renal function in this in vivo model of inflammatory renal disease. Agmatine can also markedly reduce proliferative changes by inhibiting ODC activity, an effect previously demonstrated in vitro.
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Acknowledgments |
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Footnotes |
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S.I. and R.C. share first-author status.
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and IFN-
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