Published online before print May 10, 2001, doi: 10.1161/hh1001.091521
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© 2001 American Heart Association, Inc.
Article |
Exacerbation of Chronic Renovascular Hypertension and Acute Renal Failure in Heme Oxygenase-1–Deficient Mice
From the Program of Developmental Cardiovascular Biology (P.W., A.P.P., I.M.C., Z.Y.W., A.P., K.M., N.D., M.D.L., S.-F. Y., M.-E. L., M.A.P.), the Cardiovascular (S.F.-Y., M.-E.L.) and Pulmonary and Critical Care Divisions (M.D.L., M.A.P.), and the Department of Pathology (H.G.R.), Brigham and Women’s Hospital, Boston, Mass; the Department of Medicine (A.P., M.D.L., S.-F.Y., M.-E.L., M.A.P.), Harvard Medical School, Boston, Mass.
Correspondence to Mark A. Perrella, Pulmonary and Critical Care Division, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail mperrella{at}rics.bwh.harvard.edu
Abstract
Abstract—Heme oxygenase (HO) is a cytoprotective enzyme that degrades heme (a potent oxidant) to generate carbon monoxide (a vasodilatory gas that has anti-inflammatory properties), bilirubin (an antioxidant derived from biliverdin), and iron (sequestered by ferritin). Because of properties of HO and its products, we hypothesized that HO would be important for the regulation of blood pressure and ischemic injury. We studied chronic renovascular hypertension in mice deficient in the inducible isoform of HO (HO-1) using a one kidney–one clip (1K1C) model of disease. Systolic blood pressure was not different between wild-type (HO-1+/+), heterozygous (HO-1+/-), and homozygous null (HO-1-/-) mice at baseline. After 1K1C surgery, HO-1+/+ mice developed hypertension (140±2 mm Hg) and cardiac hypertrophy (cardiac weight index of 5.0±0.2 mg/g) compared with sham-operated HO-1+/+ mice (108±5 mm Hg and 4.1±0.1 mg/g, respectively). However, 1K1C produced more severe hypertension (164±2 mm Hg) and cardiac hypertrophy (6.9±0.6 mg/g) in HO-1-/- mice. HO-1-/- mice also experienced a high rate of death (56%) within 72 hours after 1K1C surgery compared with HO-1+/+ (25%) and HO-1+/- (28%) mice. Assessment of renal function showed a significantly higher plasma creatinine in HO-1-/- mice compared with HO-1+/- mice. Histological analysis of kidneys from 1K1C HO-1-/- mice revealed extensive ischemic injury at the corticomedullary junction, whereas kidneys from sham HO-1-/- and 1K1C HO-1+/- mice appeared normal. Taken together, these data suggest that chronic deficiency of HO-1 does not alter basal blood pressure; however, in the 1K1C model an absence of HO-1 leads to more severe renovascular hypertension and cardiac hypertrophy. Moreover, renal artery clipping leads to an acute increase in ischemic damage and death in the absence of HO-1.
Key Words: hypertension • ischemia • oxidative injury • endothelin
Heme oxygenase (HO) is the enzyme that catalyzes the initial reaction in heme catabolism.1 The inducible isoform, HO-1, is upregulated by diverse stimuli including mediators of oxidative stress.2 3 HO-1 is a cytoprotective enzyme4 5 6 that degrades heme (a potent oxidant) to generate carbon monoxide (CO, a vasodilatory gas that has anti-inflammatory properties), bilirubin (an antioxidant derived from biliverdin), and iron (sequestered by ferritin). Because of properties of HO-1 and its products, it is believed that HO-1 may play an important role in cellular antioxidant defense mechanisms.
Sacerdoti et al7 and Escalante et al8 have demonstrated that either acute or chronic administration of an inducer of HO-1 (stannous chloride) to spontaneously hypertensive rats led to a normalization of blood pressure. Other inducers of HO-1 or HO substrates have also been shown to decrease blood pressure in hypertensive rats.9 10 11 This response is not limited to the systemic vasculature, because inducers of HO-1 can prevent the development of hypoxic pulmonary hypertension.12 In addition, it has been demonstrated that treatment of normal13 or endotoxemic14 rats with inhibitors of HO (metalloporphyrins) produces an increase in systemic arterial pressure. Because biliverdin itself has not been associated with the regulation of blood pressure,13 these studies provided evidence that CO via the HO system may contribute to the regulation of systemic blood pressure. One way in which CO regulates blood pressure is by producing cGMP,2 15 16 17 which has vasodilatory properties.
Beyond the vasodilatory effect of CO through cGMP, Morita and Kourembanas18 have shown that vascular smooth muscle cell–derived CO inhibits production of the potent vasoconstrictor endothelin (ET)-1. This inhibition may contribute to the effects of CO on vascular tone and blood pressure. Investigators have also demonstrated that angiotensin II–induced hypertension promotes an induction of HO-1,19 20 21 suggesting that upregulation of endogenous HO-1 may attempt to counteract the hypertensive effect of angiotensin II.
An organ that plays a predominant role in the chronic regulation of blood pressure is the kidney. Interestingly, several lines of evidence suggest that beyond its potential effects on systemic vascular tone and blood pressure, HO-1 modulates renal function.22 HO-1 is induced in rat models of acute renal injury including glycerol-induced renal failure,5 nephrotoxic serum nephritis,23 cisplatin nephrotoxicity,24 and ischemia/reperfusion–induced renal failure.25 26 Increased expression of HO-1 has been noted in renal tubules,5 23 renal glomeruli,27 and inflammatory cells infiltrating the kidney,28 depending on the model studied. Moreover, in some of these models, chemical inhibitors of HO activity have been shown to worsen renal damage,5 24 26 suggesting a protective role for HO-1. Unfortunately, these inhibitors are not selective for HO-1, they affect HO-2 and other enzyme systems, and they may have undesirable side effects.29 Thus, the generation of HO-1 null mice30 31 allows a means to specifically investigate the role of HO-1 in different disease processes.
To evaluate the role of HO-1 in the control of systemic blood pressure and renal protection, we used a one kidney–one clip (1K1C) model of renovascular hypertension.32 33 This model consists of a unilateral nephrectomy and a partial occlusion of the renal artery of the remaining kidney that leads to a reduction in renal perfusion. In the 1K1C model, fluid retention by the single stenotic kidney leads to volume-dependent hypertension. The more recent development of this model in mice33 allows for the study of renovascular hypertension in HO-1 null mice.
Materials and Methods
Mouse Model of Renovascular
Hypertension
Mice that were wild-type (+/+), heterozygous (+/-),
or homozygous null (-/-) for targeted disruption of
HO-131 were studied. These
mice were maintained on a 129SvxBALB/c genetic background, and
littermates were used for the studies. One kidney-one clip surgery was
performed on mice that were 5 weeks of age, as previously
described.33 Briefly, a
0.12-mm clip was inserted on the left renal artery to chronically
reduce perfusion pressure, and a right nephrectomy was performed. As
controls, mice also underwent the same procedure, with the exception
that no clip was applied. The mice were killed 28 hours or 9 weeks
after surgery. Kidney tissue for mRNA analysis and plasma
samples for creatinine analysis were collected and
stored at -80°C and -20°C, respectively, until further
processing. Because ET-1 may play a detrimental role in
ischemia-induced renal
injury,34 35 36
pilot studies were performed to select the most optimal dose of
ETA receptor antagonist to study,
using doses of 2.5 and 5.0 mg/kg. From these pilot studies, the
ETA receptor antagonist BQ-123
(Calbiochem-Novabiochem
Corp) was administered intraperitoneally (5.0 mg/kg
IP) 2 hours before and 12 hours after 1K1C surgery. The Harvard Medical
Area Standing Committee on Animals approved the
protocol.
Blood Pressure Measurements and Assessment of
Cardiac Weight Index
A tail-cuff method was used to measure
systolic blood pressure (SBP), as described
previously.37 Mice were
trained by placing them in restraints, 1 hour daily, for 10 days before
the experiments. Once fully trained, conscious mice were restrained and
gently warmed using a heating lamp. An occlusion cuff and a
piezoelectric pulse sensor were placed around their tail
(Kent Scientific), and SBP was measured after a
15-minute acclimatization period. A minimum of eight serial
measurements was made and the average value was calculated
(Mac Lab software, version 3.5, AD Instruments).
Both training and blood pressure measurements were performed at the
same time each day (afternoon). Nine weeks after surgery, the mice were
killed and their hearts removed. Cardiac weight index (CWI) was
calculated as CWI=heart wet weight (mg)/body weight
(g).
Biochemical Measurement of
Creatinine
Twenty-eight hours after surgery, blood was obtained
from the retro-orbital sinus, centrifuged at
2500g for 10 minutes at 4°C,
and stored at -20°C. Plasma creatinine (Cr) levels were
measured using a commercial kit (Sigma),
according to the manufacturer’s recommendations.
Northern Blot Analysis
Total RNA was obtained from mouse kidneys by
guanidinium isothiocyanate extraction and silica-gel-membrane spin
technology (RNeasy midi kit,
Qiagen). RNA was fractionated on a 1.3%
formaldehyde-agarose gel and transferred to nitrocellulose filters. The
filters were hybridized at 68°C for 2 hours with a
32P-labeled rat HO-1 probe or a mouse ET-1
probe in QuikHyb solution (Stratagene) as
described previously.37 The
hybridized filters were then washed in 30 mmol/L sodium chloride,
3 mmol/L sodium citrate, and 0.1% SDS at 55°C and
autoradiographed with Kodak XAR film. To assess
for differences in RNA loading, the filters were washed in a 50%
formamide solution at 80°C and rehybridized with a
32P-labeled oligonucleotide
probe complementary to 18S ribosomal RNA.
Histological and
Immunohistochemical Analysis
Kidneys were harvested from the mice 28 hours after
1K1C surgery, washed in PBS, and fixed in 10% formalin overnight at
4°C. The specimens were processed, embedded, and sectioned at a
thickness of 5 µm. Immunocytochemical staining was performed next. To
reduce nonspecific binding, the sections were incubated in cadenza
buffer (Shandon) containing 10% normal goat
serum. Rabbit polyclonal antibody against rat HO-1
(SPA895, StressGen Biotechnologies) was applied
for 1 hour at room temperature and then overnight at 4°C at a
dilution of 1:400. Sections were rinsed twice with cadenza buffer and
incubated with biotinylated goat anti-rabbit IgG at a dilution of 1:200
for 1 hour at room temperature. They were then rinsed with cadenza
buffer twice and incubated with avidin-biotin complex
(Vectastain ABC kit, Vector Labs) for 1 hour at
room temperature. After washing twice with cadenza buffer, the tissue
sections were developed using the Vector DAB substrate kit
(Vector Laboratory) and counterstained with 1%
methyl green. The presence of HO-1 was indicated by the development of
a brown color. Periodic acid-Schiff (PAS) staining was also performed
on the kidney sections, as previously
described.38
Statistics
Where indicated, comparisons between groups were made
by factorial ANOVA followed by Fisher’s least-significant difference
test when appropriate. Survival comparisons between groups were made by
the 
2 goodness-of-fit test. Statistical
significance was accepted at
P<0.05. Data are expressed as
mean±SEM.
Results
Enhanced Renovascular Hypertension and Cardiac
Hypertrophic Response in HO-1-/-
Mice
Under basal conditions, SBP was not different between
HO-1+/+ (106±3 mm Hg),
HO-1+/- (99±2 mm Hg), and
HO-1-/- (101±2 mm Hg) mice. Mice
were then challenged with the 1K1C model of renovascular hypertension.
We measured SBP 9 weeks after surgery in sham and 1K1C mice
(Figure 1
). In sham-operated mice, SBP was similar in
HO-1+/+,
HO-1+/-, and
HO-1-/- mice (108±5, 105±4,
107±4 mm Hg, respectively). As expected, 1K1C surgery led to a
chronic increase in SBP in HO-1+/+ mice
(140±2 mm Hg) and a similar increase in
HO-1+/- mice (130±2 mm Hg).
However, SBP was significantly higher in 1K1C
HO-1-/- mice (164±2 mm Hg). These
data suggest that although not necessary for the maintenance of
normotension in intact mice, HO-1 may play a compensatory role in
chronic renovascular hypertension.
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P<0.05 vs all other groups.
CWI was also measured to assess cardiac
hypertrophy in the three genotypes of mice after
sham or 1K1C surgery. In all three genotypes, 1K1C mice
developed increased CWI compared with their sham controls
(Figure 2). However, similar to the SBP response,
HO-1-/- mice developed more severe
cardiac hypertrophy (6.9±0.6 mg/g) than
HO-1+/+ (5.0±0.2 mg/g) and
HO-1+/- (5.3±0.1 mg/g) mice after 9 weeks
of 1K1C-induced renovascular hypertension
(Figure 2). Whereas CWI was increased in
HO-1-/- mice, total body weight was not
different (P=0.64, n=6 to 9
mice/genotype) between HO-1-/-
mice (22.3±1.0 g), HO-1+/+ (22.7±1.2 g),
and HO-1+/- (23.8±0.8 g)
mice.
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Increased Mortality Rate in
HO-1-/- Mice After 1K1C Surgery
In the original report on the 1K1C model of
renovascular hypertension in
mice,33 an acute mortality
rate of 
25% was observed after surgery. These animals developed
renal infarctions and subsequent organ failure. Strikingly, acute
mortality rate was markedly higher in
HO-1-/- mice (56%) compared with
HO-1+/+ (25%) and
HO-1+/- (28%) mice after 1K1C surgery
(Table).
Within 72 hours after the 1K1C procedure, 14 of 25 mice in the
HO-1-/- group died. Acute mortality rate
was not increased in sham-operated 1K1C
HO-1-/- mice. In fact, there were no
deaths in sham-operated mice of any group. This increased mortality
rate was not restricted to the early time points after 1K1C surgery,
because the mortality rate increased to 84% in
HO-1-/- mice after 9 weeks, whereas no
late deaths (after 72 hours) were noted in the
HO-1+/+ and
HO-1+/- mice.
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Acute Renal Failure in
HO-1-/- Mice After 1K1C
Surgery
The finding that a reduction in renal perfusion leads
to an increased mortality rate in
HO-1-/- mice prompted us to evaluate
renal function shortly after clipping. We chose to assess the mice 28
hours after surgery because we have witnessed anephric mice die as
early as 28 hours postoperatively. Moreover, we focused on
HO-1+/- mice (not different from
HO-1+/+ mice) compared with
HO-1-/- mice. In sham-operated
HO-1+/- and
HO-1-/- mice, plasma Cr concentration
was not different between the two groups (32.9±1.3 versus 32.7±0.7
µmol/L respectively,
Figure 3). After 1K1C surgery, plasma Cr concentration did
not increase significantly in HO-1+/- mice
(46.7±6.2 µmol/L); however, it increased markedly in
HO-1-/- mice (83.3±17.2 µmol/L).
These data suggest that kidneys from
HO-1-/- mice are more susceptible to
ischemic injury.
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Regulation of HO-1 and ET-1 Gene Expression
After 1K1C Surgery
To further investigate the role of HO-1 in the
adaptation of the kidney to a reduction in perfusion, we assessed the
renal expression of HO-1 mRNA 28 hours after clipping
HO-1+/- mice. Whereas HO-1 was expressed
only at a low level in sham-operated mice, it was significantly induced
after 1K1C surgery in HO-1+/- mice
(Figure 4A).
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Studies have demonstrated that ET-1 may play a detrimental
role in the course of acute renal
failure.34 Because
HO-1–derived CO is known to inhibit the expression of
ET-1,18 we hypothesized that
in HO-1-/- mice there may be an
induction of ET-1 after 1K1C surgery. We performed Northern blot
analysis to evaluate renal ET-1 mRNA levels 28 hours after 1K1C
or sham surgery. ET-1 mRNA was expressed at low levels in
HO-1+/- and
HO-1-/- mice after sham surgery
(Figure 4B
), and renal artery clipping did not induce ET-1
mRNA at this time point in HO-1+/- mice.
In contrast, ET-1 mRNA was induced in 1K1C
HO-1-/- mice
(Figure 4B).
Effect of ETA Receptor
Antagonist on Acute Renal Failure in
HO-1-/- Mice After 1K1C Surgery
Administration of an antagonist to the
ETA receptor (ETARA) had
no effect on plasma Cr concentrations of
HO-1+/- mice after renal artery clipping
(Figure 5). However, the increase in plasma Cr in
HO-1-/- mice (95.4±18.6 µmol/L) after
1K1C surgery was prevented by administration of the
ETARA (49.4±14.4 µmol/L). Moreover, all
HO-1-/- mice receiving
ETARA (n=9) survived the acute period after
renal artery clipping.
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HO-1 Expression and Kidney Damage Associated
With 1K1C Surgery
Kidneys were harvested from the mice 28 hours after
1K1C surgery. Immunohistochemical staining was then performed for HO-1
(Figures 6A and 6B). After 1K1C surgery, increased expression
of HO-1 was noted in the renal tubules of
HO-1+/- mice
(Figure 6B, brown staining, arrows). Interestingly, staining
was not seen in the glomeruli.
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PAS staining was next performed
(Figures 6C through 6F) on kidney tissue from
HO-1+/- and
HO-1-/- mice in the presence (+) or
absence (-) of an antagonist to
ETARA. In HO-1+/-
mice in which the expression of HO-1 is increased by renal artery
clipping, 1K1C surgery did not induce ischemic damage in the
presence or absence of the ETARA
(Figures 6C and 6E). However, in
HO-1-/- mice, clipping of the renal
artery produced ischemic damage predominating in the renal
tubules of the outer medulla
(Figure 6D). The architecture of the
corticomedullary junction
(Figure 6D, arrowheads) was distorted in
HO-1-/- mice with evidence of acute
tubular necrosis in comparison with
HO-1+/- mice
(Figures 6C, arrowheads). Administration of
ETARA, 5.0 mg/kg IP, before and 12 hours after
1K1C surgery, prevented this ischemic damage
(Figure 6F).
Discussion
HO-1 has been implicated in the control of blood
pressure and the regulation of vascular tone. Thus, one goal of this
study was to determine the importance of endogenous HO-1 on
blood pressure regulation. No difference in SBP was evident between
HO-1+/+,
HO-1+/-, and
HO-1-/- mice at baseline (see Results
and
Figure 1, sham mice). These data revealed that different
from the acute inhibition of HO enzymes in normal
animals,13 the chronic
absence of HO-1 does not lead to a sustained increase in SBP. This may
suggest a role for HO-2 in blood pressure regulation in the setting of
acute HO inhibition, or that during the chronic absence of HO-1
compensatory mechanisms prevent an increase in SBP. We next studied the
effect of HO-1 absence on a model of renovascular hypertension. In the
1K1C model, one kidney is removed while the remaining kidney undergoes
arterial constriction. In response to this decrease in
renal perfusion pressure, plasma renin levels rapidly rise with a
subsequent increase in circulating angiotensin II
levels.32 33 This
results in the early hypertensive response. Chronically, the 1K1C
procedure leads to volume retention by the single clipped kidney and a
volume-dependent, low-renin
hypertension.32 33
Because HO-1 expression is regulated by the administration of
angiotensin
II19 20 21
and that inducers of HO-1 normalize blood pressure in models of
hypertension,7 8 9 10 11
we hypothesized that endogenous HO-1 may attempt to
counteract the development of renovascular hypertension. Indeed, in the
absence of endogenous HO-1, there was an exacerbation of
chronic renovascular hypertension after the 1K1C procedure
(Figure 1).
Associated with the hypertension of renal artery clipping,
the myocardium undergoes a hypertrophic response as an
adaptation to increased blood
pressure.33 As shown in
Figure 2, cardiac mass was significantly greater in
HO-1-/- mice compared with
HO-1+/+ and
HO-1+/- mice. This response paralleled
the hypertensive response shown in
Figure 1. However, Seki et
al39 have shown in
spontaneously hypertensive rats that chronic administration of an
inducer of HO-1 (stannous chloride), at a dose that does not alter
systemic blood pressure, can attenuate the development of cardiac
hypertrophy. This may suggest that beyond a regulation of
systemic blood pressure, HO-1 may have independent effects on the
development of cardiac hypertrophy. Important to the
development of renovascular hypertension, Raju et
al40 have previously shown
that bilateral renal artery ischemia followed by reperfusion of
the kidneys can induce HO-1 expression and increase cGMP levels in the
heart. It was speculated that hemodynamic stress caused
by occlusion of the renal arteries led to activation of HO-1 gene
expression in the heart.
Depending on the severity of ischemia, renal artery
occlusion can lead to injury and dysfunction of the kidney.
Ischemic renal injury is characterized by intrarenal
vasoconstriction, leading to reduced glomerular plasma flow
and filtration rate, and reduced oxygen delivery to the tubules of the
outer medulla.41 HO has been
implicated as a mediator of medullary blood
flow.42 However, this renal
ischemic response is often attributed to the release of
endogenous vasoconstrictors, such as
ET-1.43 The importance of
ET-1 in ischemia-induced acute renal failure has been
demonstrated by the beneficial effects of ET receptor
antagonists on the pathophysiological
consequences of this
process.34 35 36
In our study, renal artery clipping led to an induction of HO-1 mRNA
(Figure 4A), and increased HO-1 protein was localized to the
renal tubules of HO-1+/- mice
(Figure 6B). In the setting of this HO-1 induction,
ischemia induced by the renal artery clipping was not severe
enough to cause an acute increase in plasma Cr levels
(Figure 3) or structural damage to the kidney
(Figure 6C). However, in the absence of HO-1, mice subjected
to the same clipping experienced an increased mortality rate
(Table),
increased plasma Cr levels
(Figure 3), and ischemic damage to the renal tubules
of the outer medulla
(Figure 6D). By administering an antagonist to
ETARA, the increase in plasma Cr
(Figure 5) and the ischemic damage
(Figure 6F) were prevented. Taken together, these data
suggest that in the absence of HO-1 and the presence of increased renal
ET-1, kidneys are at increased risk for acute ischemic damage
and subsequent failure leading to death. Because the 1K1C model of
renovascular hypertension is a volume-dependent process initiated by a
limitation in renal function, we believe that the exacerbated
hypertension in HO-1-/- mice reflects
progressive renal injury contributed to by elevated levels of renal
ET-1. More severe tubular injury and renal failure have also been
demonstrated in HO-1-/- mice subjected
to the glycerol model of heme protein
toxicity44 and
cisplatin-induced
nephrotoxicity.45
In the present study, the predisposition for ischemic renal failure in HO-1-/- mice may well relate to an environment prone to vasoconstriction in the absence of HO-1–derived CO and the increase in renal ET-1 levels. Moreover, because HO-1 plays an important role in cellular antioxidant defense mechanisms, the absence of HO-1 leads to increased susceptibility to tissue oxidative damage.30 31 37 HO-1 is an important mediator of inflammation2 46 47 that may contribute to renal injury in the setting of ischemia,48 and HO-1–derived CO has recently been suggested to have anti-inflammatory effects through a pathway involving mitogen-activated protein kinases.49
In summary, data from our study suggest that chronic deficiency of HO-1 does not alter basal blood pressure; however, in the 1K1C model an absence of HO-1 leads to more severe renovascular hypertension and cardiac hypertrophy. Moreover, renal artery clipping leads to increased ischemic damage and death in the absence of HO-1, and ET-1 appears to play an important role in the pathophysiology of this acute renal ischemic damage. These data provide further support for the importance of endogenous HO-1, a cytoprotective enzyme, in the regulation of cardiovascular function and the mediation of pathophysiological stimuli leading to oxidative stress.
Acknowledgments
This study was supported in part by National Institutes of Health Grants HL60788 and GM53249 (to M.A.P.) and American Heart Grant-in-Aid awards (to M.A.P. and S.-F.Y.), grants from Novartis and the SICPA Foundation (to P.W.), and a grant from the Bristol-Myers Squibb Pharmaceutical Research Institute. We thank Bonna Ith for his technical assistance.
Footnotes
Original received March 14, 2001; revision received April 10, 2001; accepted April 16, 2001.
1 Both authors contributed equally to this study. 
References
1.
Tenhunen
R, Marver HS, Schmid R. The enzymatic conversion of heme to bilirubin
by microsomal heme oxygenase.
Proc Natl Acad Sci
U S A. 1968;61:748–755.
2.
Maines MD. The heme
oxygenase system: a regulator of second messenger gases.
Annu Rev Pharmacol Toxicol. 1997;37:517–554.
3.
Schacter BA. Heme
catabolism by heme oxygenase: physiology, regulation, and
mechanism of action. Semin
Hematol. 1988;25:349–369.
4.
Keyse SM, Tyrrell
RM. Both near ultraviolet radiation and the oxidizing agent hydrogen
peroxide induce a 32-kDa stress protein in normal human skin
fibroblasts. J Biol Chem. 1987;262:14821–14825.
5.
Nath KA, Balla G,
Vercellotti GM, Balla J, Jacob HS, Levitt MD, Rosenberg ME. Induction
of heme oxygenase is a rapid, protective response in
rhabdomyolysis in the rat. J Clin
Invest. 1992;90:267–270.
6.
Otterbein LE, Choi
AMK. Heme oxygenase: colors of defense against cellular
stress. Am J Physiol Lung Cell Mol
Physiol. 2000;279:L1029–L1037.
7.
Sacerdoti D,
Escalante B, Abraham NG, McGiff JC, Levere RD, Schwartzman ML.
Treatment with tin prevents the development of hypertension in
spontaneously hypertensive rats.
Science. 1989;243:388–390.
8.
Escalante B,
Sacerdoti D, Davidian MM, Laniado-Schwartzman M, McGiff JC. Chronic
treatment with tin normalizes blood pressure in spontaneously
hypertensive rats.
Hypertension. 1991;17(6 pt 1):776–779.
9.
Levere RD, Martasek
P, Escalante B, Schwartzman ML, Abraham NG. Effect of heme arginate
administration on blood pressure in spontaneously hypertensive rats.
J Clin Invest. 1990;86:213–219.
10.
Martasek P, Schwartzman ML, Goodman AI, Solangi KB, Levere RD, Abraham NG. Hemin and L-arginine regulation
of blood pressure in spontaneous hypertensive rats. J Am Soc Nephrol. 1991;2:1078–1084.
11.
Johnson RA,
Lavesa M, Deseyn K, Scholer MJ, Nasjletti A. Heme oxygenase
substrates acutely lower blood pressure in hypertensive rats.
Am J Physiol. 1996;271:H1132–H1138.
12.
Christou H,
Morita T, Hsieh C-M, Koike H, Arkonac B, Perrella MA, Kourembanas S.
Prevention of hypoxia-induced pulmonary hypertension by
enhancement of endogenous heme oxygenase-1 in
the rat. Circ Res. 2000;86:1224–1229.
13.
Johnson RA,
Lavesa M, Askari B, Abraham NG, Nasjletti A. A heme
oxygenase product, presumably carbon monoxide, mediates
a vasodepressor function in rats.
Hypertension. 1995;25:166–169.
14.
Yet S-F,
Pellacani A, Patterson C, Tan L, Folta SC, Foster L, Lee W-S, Hsieh
C-M, Perrella MA. Induction of heme oxygenase-1 expression
in vascular smooth muscle cells: a link to endotoxic shock.
J Biol Chem. 1997;272:4295–4301.
15.
Marks GS, Brien
JF, Nakatsu K, McLaughlin BE. Does carbon monoxide have a
physiological function?
Trends Pharmacol Sci. 1991;12:185–188.
16.
Morita T,
Perrella MA, Lee M-E, Kourembanas S. Smooth muscle cell-derived carbon
monoxide is a regulator of vascular cGMP.
Proc Natl Acad Sci
U S A. 1995;92:1475–1479.
17.
Christodoulides
N, Durante W, Kroll MH, Schafer AI. Vascular smooth muscle cell heme
oxygenases generate guanylyl cyclase-stimulatory carbon
monoxide. Circulation. 1995;91:2306–2309.
18.
Morita T,
Kourembanas S. Endothelial cell expression of
vasoconstrictors and growth factors is regulated by smooth muscle
cell-derived carbon monoxide. J Clin
Invest. 1995;96:2676–2682.
19.
Ishizaka N, De
Leon H, Laursen JB, Fukui T, Wilcox JN, De Keulenaer F, Griendling KK,
Alexander RW. Angiotensin II–induced hypertension
increases heme oxygenase-1 expression in rat aorta.
Circulation. 1997;96:1923–1929.
20.
Haugen EN, Croatt
AJ, Nath KA. Angiotensin II induces renal oxidant stress in
vivo and heme oxygenase-1 in vivo and in vitro.
Kidney Int. 2000;58:144–152.
21.
Aizawa T,
Ishizaka N, Taguchi J, Nagai R, Mori I, Tang SS, Ingelfinger JR, Ohno
M. Heme oxygenase-1 is upregulated in the kidney of
angiotensin II–induced hypertensive rats: possible role in
renoprotection. Hypertension. 2000;35:800–806.
22.
Agarwal A, Nick
HS. Renal response to tissue injury: lessons from heme
oxygenase-1 gene ablation and expression.
J Am Soc Nephrol. 2000;11:965–973.
23.
Vogt BA, Shanley
TP, Croatt A, Alam J, Johnson KJ, Nath KA. Glomerular
inflammation induces resistance to tubular injury in the rat: a novel
form of acquired, heme oxygenase-dependent resistance to
renal injury. J Clin
Invest. 1996;98:2139–2145.
24.
Agarwal A, Balla
J, Alam J, Croatt AJ, Nath KA. Induction of heme oxygenase
in toxic renal injury: a protective role in cisplatin nephrotoxicity in
the rat. Kidney Int. 1995;48:1298–1307.
25.
Maines MD, Mayer
RD, Ewing JF, McCoubrey WKJ. Induction of kidney heme
oxygenase-1 (HSP32) mRNA and protein by
ischemia/reperfusion: possible role of heme as both promoter of
tissue damage and regulator of HSP32.
J Pharmacol Exp Ther. 1993;264:457–462.
26.
Shimizu H,
Takahashi T, Suzuki T, Yamasaki A, Fujiwara T, Odaka Y, Hirakawa M,
Fujita H, Akagi R. Protective effect of heme oxygenase
induction in ischemic acute renal failure.
Crit Care Med. 2000;28:809–817.
27.
Hayashi K, Haneda
M, Koya D, Maeda S, Isshiki K, Inoki K, Sugimoto T, Kikkawa R.
Preferential enhancement of glomerular heme oxygeanse-1
(HO-1) expression in diabetic rats and its reversal by antioxidants.
J Am Soc Nephrol. 1999;10:682. Abstract.
28.
Agarwal A, Kim Y,
Matas AJ, Alam J, Nath KA. Gas-generating systems in acute renal
allograft rejection in the rat: co-induction of heme
oxygenase and nitric oxide synthase.
Transplantation. 1996;61:93–98.
29.
Grundemar L, Ny
L. Pitfalls using metalloporphyrins in carbon monoxide research.
Trends Pharmacol Sci. 1997;18:193–195.
30.
Poss KD, Tonegawa
S. Reduced stress defense in heme oxygenase 1-deficient
cells. Proc Natl Acad Sci
U S A. 1997;94:10925–10930.
31.
Yet S-F, Perrella
MA, Layne MD, Hsieh C-M, Maemura K, Kobzik L, Wiesel P, Christou H,
Kourembanas S, Lee M-E. Hypoxia induces severe right
ventricular dilatation and infarction in heme
oxygenase-1 null mice. J
Clin Invest. 1999;103:R23–R29.
32.
Goldblatt H,
Lynch J, Hanzal RF, Summerville WW. Studies on experimental
hypertension: production of persistent elevation of
systolic blood pressure by means of renal ischemia.
J Exp Med. 1934;59:347–379.
33.
Wiesel P,
Mazzolai L, Nussberger J, Pedrazzini T. Two-kidney, one clip and
one-kidney, one clip hypertension in mice.
Hypertension. 1997;29:1025–1030.
34.
Gellai M, Jugus
M, Fletcher T, DeWolf R, Nambi P. Reversal of postischemic
acute renal failure with a selective endothelin A receptor
antagonist in the rat. J
Clin Invest. 1994;93:900–906.
35.
Mino N, Kobayashi
M, Nakajima A, Amano H, Shimamoto K, Ishikawa K, Watanabe K, Nishikibe
M, Yano M, Ikemoto F. Protective effect of a selective endothelin
receptor antagonist, BQ-123, in ischemic acute
renal failure in rats. Eur J
Pharmacol. 1992;221:77-83.
36.
Chan L,
Chittinandana A, Shapiro JI, Shanley PF, Schrier RW. Effect of an
endothelin-receptor antagonist on ischemic acute
renal failure. Am J
Physiol. 1994;266:F135–F138.
37.
Wiesel P, Patel
AP, DiFonzo N, Marria PB, Sim SU, Pellacani A, Maemura K, LeBlanc BW,
Marino K, Doerschuk CM, Yet S-F, Lee M-E, Perrella MA.
Endotoxin-induced mortality is related to increased oxidative stress
and end-organ dysfunction, not refractory hypotension, in heme
oxygenase-1 deficient mice.
Circulation. 2000;102:3015–3022.
38.
Carson FL.
Histotechnology: A Self-Instructional
Text. 2nd ed. Chicago, Ill: ASCP Press:
1997.
39.
Seki T, Naruse M,
Naruse K, Yoshimoto T, Tanabe A, Seki M, Tago K, Imaki T, Demura R,
Demura H. Induction of heme oxygenase produces
load-independent cardioprotective effects in hypertensive rats.
Life Sci. 1999;65:1077–1086.
40.
Raju VS, Maines
MD. Renal ischemia/reperfusion up-regulates heme
oxygenase-1 (HSP32) expression and increases cGMP in rat
heart. J Pharmacol Exp
Ther. 1996;277:1814–1822.
41.
Kumar V, Cotran
RS, Robbins SL. The kidney and its collecting system. In: Kumar V,
Cotran RS, Robbins SL, eds. Basic
Pathology. 6th ed. Philadelphia, Pa: WB Saunders Co;
1997:439–469.
42.
Zou AP,
Billington H, Su N, Cowley AWJ. Expression and actions of heme
oxygenase in the renal medulla of rats.
Hypertension. 2000;35:342–347.
43.
Hunley TE, Kon V.
Endothelin in ischemic acute renal failure.
Curr Opin Nephrol Hypertens. 1997;6:394–400.
44.
Nath KA, Haggard
JJ, Croatt AJ, Grande JP, Poss KD, Alam J. The indispensability of heme
oxygenase-1 in protecting against acute heme
protein-induced toxicity in vivo. Am
J Pathol. 2000;156:1527–1535.
45.
Shiraishi F,
Curtis LM, Truong L, Poss K, Visner GA, Madsen K, Nick HS, Agarwal A.
Heme oxygenase-1 gene ablation or expression modulates
cisplatin-induced renal tubular apoptosis.
Am J Physiol. 2000;278:F726–F736.
46.
Willis D, Moore
AR, Frederick R, Willoughby DA. Heme oxygenase: a novel
target for the modulation of the inflammatory response.
Nat Med. 1996;2:87–90.
47.
Soares MP, Lin Y,
Anrather J, Csizmadia E, Takigami K, Sato K, Grey ST, Colvin RB, Choi
AM, Poss KD, Bach FH. Expression of heme oxygenase-1 can
determine cardiac xenograft survival. Nat
Med. 1998;4:1073–1077.
48.
Caramelo C,
Arroyo MVA. Polymorphonuclear neutrophils in acute renal failure:
new insights. Nephrol Dial
Transplant. 1998;13:2185–2188.
49.
Otterbein LE,
Bach FH, Alam J, Soares M, Lu HT, Wysk M, Davies RJ, Flavell RA, Choi
AMK. Carbon monoxide has anti-inflammatory effects involving the
mitogen-activated protein kinase pathway.
Nat Med. 2000;6:422–428.
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