Inhibition of heme oxygenase decreases sodium and fluid absorption in the loop of Henle
Tong Wang,1
Hyacinth Sterling,2
Wei A. Shao,1
QingShang Yan,1
Matthew A. Bailey,1
Gerhard Giebisch,1 and
Wen-Hui Wang2
1Department of Cellular and Molecular Physiology,
Yale University School of Medicine, New Haven, Connecticut 06520; and
2Department of Pharmacology, New York Medical College,
Valhalla, New York 10595
Submitted 3 April 2003
; accepted in final form 19 May 2003
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ABSTRACT
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We previously demonstrated that carbon monoxide (CO) stimulates the apical
70-pS K+ channel in the thick ascending limb (TAL) of the rat
kidney (Liu HJ, Mount DB, Nasjletti A, and Wang WH. J Clin Invest
103: 963-970, 1999). Because the apical K+ channel plays a key role
in K+ recycling, we tested the hypothesis that heme oxygenase
(HO)-dependent metabolites of heme may affect Na+ transport in the
TAL. We used in vivo microperfusion to study the effect of chromium
mesoporphyrin (CrMP), an inhibitor of HO, on fluid absorption
(Jv) and Na+ absorption
(JNa) in the loop of Henle and renal clearance methods to
examine the effect of CrMP on renal sodium excretion. Microperfusion
experiments demonstrated that addition of CrMP to the loop of Henle decreased
Jv by 13% and JNa by 20% in animals on
normal rat chow and caused a decrease in Jv (39%) and
JNa (40%) in rats on a high-K+ (HK) diet. The
effect of CrMP is the result of inhibition of HO because addition of MgPP, an
analog of CrMP that does not inhibit HO, had no effect on
Jv. Western blot analysis showed that HO-2 is expressed in
the kidney and that the level of HO-2 was significantly elevated in animals on
a HK diet. Renal clearance studies demonstrated that the infusion of CrMP
increased the excretion of urinary Na+ (ENa) and volume
(UV) without changes in glomerular filtration rate. The effect of CrMP on
ENa and UV was larger in HK rats than those kept on normal chow. We
conclude that HK intake increases HO-2 expression in the kidney and that
HO-dependent metabolites of heme, presumably CO, play a significant role in
the regulation of Na+ transport in the loop of Henle.
carbon monoxide; sodium and potassium transport; microperfusion
HEME OXYGENASE (HO) metabolizes heme molecules to produce
biliverdin, carbon monoxide (CO), and chelated iron by oxidative cleavage
(19). Three isoforms of HO
have been identified: HO-1, an inducible isoform; HO-2, a constitutively
expressed isoform; and HO-3
(19,
20). HO-1 and HO-2 are
expressed in the kidney (16,
22), and a large body of
evidence suggests that CO plays an important role in the regulation of a
variety of cell functions (6,
8). For instance, CO has been
reported to increase the production of cGMP by stimulation of guanylate
cyclase (6,
8). Also, CO is involved in the
activation of Ca2+-dependent large-conductance
K+ channels
(26-28),
which may be responsible for CO-induced vasodilation of renal arterial vessels
(26).
We previously demonstrated that inhibition of HO by chromonium
mesoporphyrin (CrMP) decreases the activity of the 70-pS K+ channel
in the thick ascending limb (TAL) of the rat kidney
(16). Because the inhibitory
effect can be reversed by CO, this suggests that CO is an HO-dependent
metabolite of heme responsible for stimulating the apical 70-pS K+
channel (16). Because these
K+ channels play a key role in K+ recycling across the
apical membrane (1,
2,
5), their inhibition by
blocking HO with CrMP is expected to decrease K+ recycling and
suppress the activity of the Na-K-2Cl cotransporter. This hypothesis was
tested by examining the effect of inhibition of HO on transepithelial
Na+ transport in the loop of Henle. We demonstrate that luminal
perfusion of CrMP significantly decreases Na+ absorption and
increases Na+ excretion in the loop of Henle. Those effects are
enhanced by increasing dietary K+ intake.
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METHODS
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Animal preparation. Male Sprague-Dawley rats (from Harlan,
Indianapolis, IN) weighing 200-250 g were used for the renal clearance and
tubule microperfusion experiments. Animals were kept on normal rat chow, a
high-K+ (HK), or a K+-deficient (KD) diet (Harlan
Teklad) and tap water until the experiment. The animals were anesthetized by
intravenous injection of Inactin (100 mg/kg) and placed on a thermostatically
controlled surgical table to maintain body temperature at 37°C. The left
jugular vein and the carotid artery were cannulated for the infusion of saline
and for collection of arterial blood samples, respectively. These methods have
been described previously (29,
30).
Renal clearance studies. Renal clearance techniques were used as
previously described (26,
27) to investigate the effects
of the HO inhibitor (CrMP) on glomerular filtration rate (GFR) and on absolute
(ENa, EK) and fractional excretion rates of
Na+ and K+ (FENa, FEK). Surgical
fluid losses were replaced with isotonic saline and a priming dose of 25
µCi of [methoxy-3H]inulin (New England Nuclear, Boston, MA) was
given in 0.5 ml isotonic saline, followed by a maintenance infusion of 0.9%
NaCl containing 25 µCi/h at a rate of 4.6 ml/h. Blood and urine samples
were collected after a 60-min equilibration period. Urine collections lasted
30 min, and blood samples were taken at the beginning and end of each
collection period. After two control periods, either CrMP (3 mg/kg) or vehicle
solution (control) was given intravenously as a bolus injection. Urine and
plasma Na+ and K+ concentrations were measured by flame
photometry (type 480 Flame Photometer, Corning Medical and Scientific,
Corning, NY) and absolute and fractional renal excretions were calculated by
standard methods (29,
30).
Microperfusion of the loop of Henle. The methods of in vivo
microperfusion of superficial loops of Henle were similar to those described
previously (29,
30). First, a loop of Henle
was selected by microperfusing a proximal tubule to locate its last loop on
the kidney surface. Then, the loop of Henle was perfused from the last loop of
the proximal tubule with a microperfusion pump at a rate of 20 nl/min. Tubule
fluid was collected from the first segment of the early distal tubule with an
oil block placed distally from the collection site. The rate of fluid
Na+ and K+ absorption in the loop of Henle was expressed
as absorption rate per loop, because the length of individual loops of Henle
in the rat has been found to vary little. Na+ and K+
concentrations in the perfusing fluid and the collected tubule fluid were
measured with a ultramicroatomic absorption spectrophotometer as previously
described (29,
30).
The composition of the perfusion fluids was as follows (in mM): 115 NaCl,
25 NaHCO3, 4 KCl, 1 CaCl2, 5 Na-acetate, 5 glucose, 5
L-alanine, 2.5 Na2HPO4, and 0.5
NaH2PO4 (pH was adjusted to 7.4 and the osmolality was
at 295 mosmol/kgH2O).
Western blot analysis. Rats were kept on different K+
diets: KD (<0.01%), HK (10% wt/wt), and normal K+ diet (NK;
Harlan Teklad) for 1 wk before use. Renal cortex and outer medulla were
dissected and homogenized as described previously
(16). Protein samples
extracted from the renal tissue were separated by electrophoresis on 8%
SDS-polyacrylamide gels and transferred to nitrocellulose membranes. The
membranes were blocked with 10% nonfat dry milk in Tris-buffered saline (TBS),
rinsed, and washed with 1% milk in Tween-TBS. The HO-1 and HO-2 antibodies
were purchased from Transduction Laboratories (Lexington, KY) and were diluted
at 1:1,000. The protein concentration used for immunoblot was 100 µg.
Materials and statistics. [methoxy-3H]inulin was
obtained from New Research Products (Boston, MA), CrMP and magnesium
protoporphyrin (MgPP) from Porphyrin Products (Logan, UT). Data are presented
as means ± SE. Control and experimental values were compared using the
unpaired Student's t-test. Dunnett's test was used for comparison of
several treatment groups with a single control group. Differences between
groups are reported as significant at P < 0.05.
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RESULTS
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We confirmed our previous findings that HO-2 is expressed in the renal
cortex and outer medulla (16)
and extended those studies to animals kept on different K+ diets.
Western blot analysis revealed that the expression of HO-2 is 150 ± 10%
(n = 4) higher in the kidney from rats on a HK diet than those kept
on a NK or KD diet (Fig.
1A). HO-2 expression is significantly diminished in the
kidney from rats on a KD diet compared with that observed in rats on a NK
diet. In contrast, HK intake did not significantly affect the expression of
HO-1 in the kidney (Fig.
1B).

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Fig. 1. Western blotting shows the presence of heme oxygenase (HO) type II
(A) and type I (B) in the renal cortex and outer medulla
from rats on normal-K+ (NK), high-K+ (HK), and
low-K+ (LK) diets. PC, positive control.
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After it was established that HO-2 expression is affected by dietary
K+ intake, the role of HO in the regulation of transport in the
loop of Henle was investigated. Microperfusion techniques were used to examine
the effect of CrMP on Na+ and K+ transport in the loop
of Henle in rats on a NK and a HK diet.
Figure 2 and
Table 1 summarize results
showing the effects of 50 µM CrMP on the rate of Na+
(JNa), fluid (JV), and K+
absorption (JK). It is apparent that perfusion of the loop
with CrMP (50 µM) inhibits Na+ and K+ absorption in
tubules from rats on NK and HK diets. It should be noted that the inhibitory
effect of CrMP on JNa is larger in rats on a HK diet than
those on a NK diet. In control rats, JNa decreased by 20%,
from 1.54 ± 0.07 to 1.22 ± 0.05 nmol/min (n = 11). In
contrast, CrMP decreased JNa by 40%, from 1.35 ±
0.07 to 0.79 ± 0.10 nmol/min (n = 10), in rats on a HK diet.
The inhibitory effect of CrMP on JK is also enhanced in
animals on a HK diet: inhibition of HO decreased JK by 64%
from 31.7 ± 3.54 to 11.2 ± 5.27 compared with a 28% decrease in
the control rats. The reason that the inhibitory effect of CrMP on
JK is larger than that on JV and
JNa may be due to backleak of K+ from the
peritubular fluid into the lumen. Huang et al.
(7) reported that inhibition of
apical K+ channels significantly increases the luminal
K+ concentration and Jamison et al.
(9) also observed that net
K+ secretion takes place at low transepithelial voltage in the TAL.
It has been previously shown that CrMP inhibits the apical 70-pS K+
channel and this could lead to attenuation of the lumen-positive potential.
Moreover, because the concentrations of K+ in the medullary
interstitial fluid may exceed that in the lumen, these two factors favor
passive influx of K+ from the peritubular fluid to lumen.

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Fig. 2. Effects of chromium mesoporphyrin (CrMP) on Na+ absorption
(JNa) in the loop of Henle in rats on a NK and HK diet.
Data are means ± SE. CrMP was added to the luminal perfusate at a
concentration of 50 µM.
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Also, JNa and JK were slightly
lower under control conditions in rats on a HK diet than in rats on a NK diet.
A similar observation has been reported previously
(25), and this modest decline
of JNa and JK may be the result of a
decrease in the driving force of Na+ and K+ transport in
HK-adapted rats. It is possible that a high plasma K+ leads to
depolarization of the basolateral membrane, which diminishes the
electrochemical gradient of Cl- exit across the basolateral
membrane. Because a decrease in Cl- diffusion across the
basolateral membrane leads to attenuation of the lumen-positive potential that
is the driving force for the paracellular Na+ and K+
absorption, Na+ and K+ transport is expected to slightly
decrease.
The effect of CrMP on JV was also significantly larger
in animals on a HK diet than that observed in rats on a NK diet. Thus infusion
of CrMP decreased fluid reabsorption in the loop of Henle.
Figure 3 and
Table 1 summarize results
demonstrating that perfusion of the loop with CrMP decreased
JV by 39% from 9.20 ± 0.48 to 5.65 ± 0.83
nl/min (n = 10) in rats on a HK diet, compared with a decrease of 13%
from 9.62 ± 0.42 to 8.35 ± 0.33 nl/min (n = 11) in rats
on a NK diet.

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Fig. 3. Effects of CrMP on fluid absorption (Jv) in the loop of
Henle from rats on a NK and HK diet. Data are means ± SE. CrMP was
added to the luminal perfusate at a concentration of 50 µM.
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To exclude the possibility of unspecific inhibitory action of CrMP, we
employed MgPP, an agent that has a similar structure to CrMP but does not
inhibit HO, to determine whether MgPP can mimic the effect of CrMP.
Figure 4 summarizes the results
from five experiments demonstrating that perfusion of the loop of Henle with
50 µM MgPP did not affect JV. These results indicate
that the effect of CrMP on JNa and JV
results from inhibition of HO.

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Fig. 4. Effects of CrMP and magnesium protoporphyrin (Mgpp) on
Jv in the loop of Henle from rats on a HK diet.
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After establishing that inhibition of HO inhibits Na+ and fluid
absorption in the loop of Henle, we extended our study by examining the
effects of CrMP on urinary Na+ and K+ excretion with
renal clearance techniques. After two 30-min baseline periods, a bolus
intravenous infusion of CrMP (3 mg/kg) was administered and four additional
urinary collections were carried out. Application of CrMP did not
significantly affect blood pressure (data not shown). Inspection of
Table 2 and
Fig. 5 shows that infusion of
HO inhibitor also did not significantly alter GFR. However, CrMP significantly
enhanced the excretion of Na+ (ENa) from a mean control
value of 0.34 ± 0.07 to 1.27 ± 0.22 meq
·min-1·100 g-1 in
rats on a NK diet (n = 5) and from 0.34 ± 0.12 to 2.42
± 0.43 meq·min-1·100
g-1 in rats on a HK diet (n = 7)
(Table 2). It is of interest
that infusion of a HO inhibitor did not significantly change urinary
K+ excretion (EK) in either rats on a NK or a HK diet
(Table 2).
Figure 5 also shows the time
course of the effect of CrMP on urinary volume (UV) in rats on a NK or HK
diet. Inhibition of HO increases UV progressively, from 0.011 (n =
10) to 0.047 ml/min (n = 5) in rats on a NK diet and from 0.015
(n = 7) to 0.042 ml/min (n = 7) in animals on a HK diet.

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Fig. 5. Effects of HO inhibitor CrMP on urinary volume and glomerular filtration
rate (GFR). Data are means ± SE. CrMP was given by intravenous (iv)
bolus injection at a concentration of 3 mg/kg in rats on NK or HK diets.
*Significantly different from control values (P <
0.05).
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Data summarized in Fig. 6
demonstrate the effects of intravenous injection of CrMP on FENa
and FEK. It is apparent that the effect of CrMP on FENa
is larger in rats on a HK diet than that observed in rats on a NK diet. Thus
inhibition of HO increased FENa from 0.012 to 2.44% in rats on a HK
diet but only from 0.031 to 1.34% in rats on a NK diet. Inspection of
Fig. 6 shows that CrMP has no
effect on FEK in rats on a NK or HK diet, although rats on a HK
diet had a higher basal level of FEK.

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Fig. 6. Effects of CrMP on fractional excretion of Na+ (FENa;
top) and K+ (FEK; bottom). CrMP was
given by iv bolus at a concentration of 3 mg/kg in rats on NK or HK diets.
*Significantly different from control values (P <
0.05).
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DISCUSSION
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Previous studies showed that dietary K+ intake affects ion
transport in the TAL (15,
17,
18). However, the mechanism by
which dietary K+ intake alters membrane transport in the TAL is
incompletely defined. We previously demonstrated that a high dietary
K+ intake increases the expression of inducible nitric oxide
synthase in the renal cortex and outer medulla and attenuates the inhibitory
effect of external Ca2+ on the apical 70-pS
K+ channel in the TAL
(3). In the present study, we
report that HO-2 expression is also augmented in the kidney from rats on a HK
diet. Because HO-2 is also expressed in the TAL
(22), the finding that a HK
intake increases HO-2 expression suggests that, like nitric oxide,
HO-dependent metabolites of heme are also involved in regulating ion transport
in the TAL from K+-adapted animals. This suggestion is supported by
the finding that infusion of CrMP, a known inhibitor of HO, lowers
Na+ reabsorption along the loop of Henle. Two lines of evidence
suggest that the effect of CrMP results from inhibition of HO-dependent
metabolism: 1) perfusion of the loop of Henle with MgPP, a CrMP
analog and weak inhibitor of HO, did not inhibit Na+ absorption in
the loop; and 2) the inhibitory effect of CrMP on Na+ and
fluid absorption was enhanced in rats on a HK diet. This is consistent with
our observation that the renal expression of HO-2 was also significantly
elevated in these animals.
The mechanism by which inhibition of HO inhibits Na+ and fluid
absorption in the loop of Henle is not fully understood. The loop of Henle
includes the late proximal tubule, the thin descending limb, the TAL, and the
early distal convoluted tubule. Immunocytochemical studies show that HO-1 and
HO-2 are expressed in the proximal tubule, TAL, and distal tubule
(22). Accordingly, the
inhibitory effect of CrMP on Na+ transport could be the result of
inhibition of Na+ transport in the late proximal tubule, TAL, or
distal convoluted tubule. The observation that CrMP significantly decreases
Jv suggests that inhibition of HO decreases the transport
in the S3 segment and descending limb, because the TAL has very low water
permeability. However, the observation that high dietary K+ intake
significantly augmented the expression of HO-2 in the renal outer medulla,
consisting mainly of the TAL, strongly suggests that this nephron segment is
an important site for the regulation of transport by HO-dependent metabolites.
One interesting observation in the present study was that the inhibitory
effect of CrMP on Na+ was greater in HK than control, despite the
fact that JNa and JK were slightly
lower in HK rats. The reduction in JNa and
JK in HK has been reported previously
(25); this modest decline of
JNa and JK may be the result of a
decrease in the driving force of Na+ and K+ transport
from lumen to cell in HK-adapted rats. The increased inhibitory action of CrMP
on JNa may be explained by our recent observation that the
ratio of 35- and 70-pS K+ channels in the TAL is significantly
modulated by HK intake. The 35-pS K+ channel was reduced from 57 to
26%, but the 70-pS channel was increased from 2 to 23% by HK. Because the
35-pS K+ channel is not regulated by HO-dependent CO production
(16), the inhibitory effect of
CrMP on Na+ absorption would be the result of inhibition of the
increased total 70-pS K+ channel activity in HK-treated rats.
The TAL is responsible for absorption of 25% filtered NaCl load and plays a
key role in the urinary concentrating ability
(1). The absorption of NaCl
involves two steps: 1) NaCl enters the cells across the apical
membrane through the Na-K-2Cl cotransporter; and 2) Na+ is
extruded across the basolateral membrane via Na-K-ATPase and Cl-
leaves the cell by diffusion along a favorable electrochemical gradient.
K+ recycling is important to maintain the activity of the Na-K-2Cl
cotransporter because it provides an adequate K+ supply for the
cotransporter (1,
2). Therefore, inhibition of
either apical K+ channels
(24) or Na-K-2Cl
cotransporters (4) could block
transepithelial NaCl absorption. In addition, if CrMP inhibits basolateral
Cl- channels, it can also lead to a decrease in transepithelial
NaCl absorption (23). However,
it is safe to conclude that the diuretic effect of CrMP results at least
partially from inhibition of apical K+ recycling by decreasing
HO-dependent metabolites such as CO, because it was previously shown that CO
can reverse the inhibitory effect of CrMP on the apical 70-pS K+
channel (16). It is most
likely that the effect of CrMP is caused by decreasing CO generation. A large
body of evidence indicates that CO plays an important role in the regulation
of several cell functions. CO has been reported to regulate blood pressure
(10-12,
14). This effect is possibly
mediated by stimulation of Ca2+-activated
large-conductance K+ channels
(27,
28). CO has also been
suggested to be involved in energy metabolism and synaptic transmission
(21). Our present data suggest
that CO may be involved in the regulation of NaCl transport in the loop of
Henle.
Three observations support the suggestion that the effect of CrMP is
mediated by inhibition of HO-2. First, the expression level of HO-1 was
significantly lower than that of HO-2 under control conditions
(22). Second, the expression
of HO-1 was not altered by a high dietary K+ intake. Third, HK
intake significantly increased the expression of HO-2 and enhanced the
inhibitory effect of CrMP on Na+ absorption in the loop of Henle.
However, the role of HO-1 in the regulation of NaCl transport in the loop
could not be completely excluded. The mechanism by which HK intake increases
HO-2 expression is not clear. High dietary K+ intake has been
demonstrated to increase plasma aldosterone levels. However, it is unlikely
that a large increase in HO-2 levels results from an increase in plasma
aldosterone levels, because low-Na+ intake did not increase HO-2
expression in renal cortex and outer medulla (unpublished observation).
Inhibition of Na+ absorption in the loop of Henle is expected to
increase Na+ delivery in the collecting tubule
(13), and this should lead to
stimulation of Na+ absorption and K+ secretion in the
initial cortical collecting tubule. However, our clearance studies
demonstrated that infusion of CrMP did not alter K+ excretion,
although Na+ excretion increased significantly. It is possible that
CrMP inhibits apical Na+ channels, apical small-conductance
secretory K+ channels, or the Ca2+-dependent
large-conductance K+ channel. CO has been shown to activate the
Ca2+-dependent large-conductance K+ channel
in smooth muscle cells
(26-28).
If inhibition of HO with CrMP would similarly block the
Ca2+-dependent large-conductance K+ channel
in principal cells, CrMP should also attenuate flow-dependent K+
secretion that is mediated by Ca2+-dependent
large-conductance K+ channels
(31). Alternatively,
inhibition of HO may stimulate K absorption in the medullary collecting duct
via H-K-ATPase (32). Further
experiments are needed to examine these possibilities.
In conclusion, HO-2 expression is regulated by K+ intake and
HO-dependent metabolites of heme such as CO regulate Na+,
K+, and fluid absorption in the loop of Henle.
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DISCLOSURES
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This work is supported by National Institutes of Health Grants HL-34300 (to
W. H. Wang) and DK-17433 (to G. Giebisch).
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ACKNOWLEDGMENTS
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The authors thank M. Steinberg for editorial assistance.
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FOOTNOTES
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Address for reprint requests and other correspondence: T. Wang, Dept. of
Cellular and Molecular Physiology, Yale School of Medicine, 333 Cedar St.,
P.O. Box 208026, New Haven, CT 06520-8026 (E-mail:
tong.wang{at}yale.edu).
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.
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