(Hypertension. 1997;29:1025-1030.)
© 1997 American Heart Association, Inc.
Articles |
Two-Kidney, One Clip and One-Kidney, One Clip Hypertension in Mice
From the Division of Hypertension, University of Lausanne (Switzerland) Medical School.
Correspondence to Thierry Pedrazzini, PhD, Division of Hypertension, University of Lausanne Medical School, CH-1011 Lausanne, Switzerland. E-mail thierry.pedrazzini{at}chuv.hospvd.ch
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Abstract |
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Abstract The mouse remains the animal of choice in transgenic experiments, creating a need for methods of evaluating the physiology of genetically modified animals. We have established and characterized two murine models of renovascular hypertension known as the two-kidney, one clip and one-kidney, one clip models. The appropriate size of the clip lumen needed to induce high blood pressure was determined to be 0.12 mm. Clips with a lumen of 0.11 mm induced a high percentage of renal infarction, and clips with a 0.13-mm opening did not produce hypertension. Four weeks after clipping, two-kidney, one clip hypertensive mice exhibited blood pressure approximately 20 mm Hg higher than their sham-operated controls. After a similar period, this increase reached almost 35 mm Hg in the one-kidney, one clip model. Depending on the model, mice develop either renin-dependent or renin-independent hypertension. Both models are characterized by the development of cardiovascular hypertrophy.
Key Words: hypertension, renovascular • mice, transgenic • renin • heart • hypertrophy
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Introduction |
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Much of our understanding of the molecular mechanisms involved in the pathophysiology of the cardiovascular system has been gained from in vitro studies. Nevertheless, the role of specific gene products in cardiovascular homeostasis should also be clarified in intact animals. Molecular biology, in particular, genetically modified animals generated by transgenic technology, has been used for investigating the basic mechanism of gene regulation and creating models of human diseases.1 2 3 The mouse remains the animal of choice in these experiments; but for the characterization of their phenotype, the physiological models established in large animals need to be adapted for studies in mice.
The renin-angiotensin system plays a major role in cardiovascular
homeostasis. The biologically active hormone Ang II has many relevant
actions related to blood pressure.4 5 In addition, Ang II
is thought to participate in the development of cardiovascular
hypertrophy by stimulating protein and DNA synthesis in smooth muscle
and cardiac cells.6 7 The hypertrophied ventricle is also
characterized by the transcription of genes encoding proteins that are
normally not expressed in the adult heart, for instance, the ANP and
fetal isoforms of contractile proteins such as 
-skeletal
actin.8
Since the original work of Goldblatt et al,9 the 2K1C and 1K1C animal models have greatly contributed to our knowledge of cardiovascular diseases. In the 2K1C model, one renal artery is constricted to chronically reduce renal perfusion, and the other kidney remains untouched. In the 1K1C model, one kidney is removed, and the other undergoes artery constriction. In both models, the earliest phase of hypertension is characterized by a rapid rise in plasma renin in response to low renal arterial pressure and by the consequent increase in circulating Ang II. However, the mechanisms of the chronic phase of hypertension differ between the two models. In the 2K1C model, hypertension is maintained by a continuously activated renin-angiotensin system because pressure diuresis of the contralateral normal kidney prevents hypervolemia. In contrast, volume retention by the single stenotic kidney of the 1K1C animal shuts off renin secretion, providing a model of low-renin, volume-dependent hypertension. Nevertheless, both models develop cardiovascular hypertrophy.10 11
Contrary to humans and rats, mice carry either one or two renin genes.12 The Ren-1 gene, which is the rat and human counterpart, is present in all strains and expressed mainly in the kidneys. Some strains carry an additional renin gene, designated Ren-2, which arose by a recent duplication of Ren-1. Ren-2 is also expressed in the kidneys but primarily in the submaxillary glands.13 To be more relevant to the situations found in rats and humans, we chose to establish the 2K1C and 1K1C models in C57BL/6 mice, which are prototypes of strains with a single renin gene.12 These two models will prove useful in pathophysiological studies of a variety of transgenic lines.
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Methods |
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Mice
Male C57BL/6 mice (Iffa Credo) with a single renin gene and approximate weight of 20 g were used at 4 to 5 weeks of age. They were maintained on tap water and a regular rodent chow (2.5 mg Na+/g) ad libitum.
Clip
For clipping, U-shaped stainless steel clips
were used (3x2x1 mm with a 2-mm-long cleft, Exidel SA). The
width of the clip opening ranged from 0.04 to 0.18 mm.
Surgery
Mice were anesthetized by halothane inhalation (1% to 2% in
oxygen). The kidney was exposed through a small flank incision,
externalized, and carefully maintained with an ophthalmic chalazion
forceps. For clipping, the renal artery of the left kidney was
individualized over a short segment by blunt dissection, and a clip was
placed close to the aorta. The kidney was then gently pushed back into
the retroperitoneal cavity. For right nephrectomy, two ligatures were
passed around the renal vascular pedicle and ureter and were tied. The
kidney was removed without the adrenal gland. The muscle layer was
sutured, and the skin incision was closed with surgical staples. A sham
procedure, which included the entire surgery with the exception of
artery clipping, was applied in control mice.
Blood Pressure and Heart Rate
The right carotid artery was exposed through a cervical incision
and isolated by blunt dissection. A catheter, formed by a length of
PE-10 tubing, was filled with a solution of glucose (5%) and heparin
(300 IU/mL) and inserted into the vessel. A minute amount of 1%
xylocaine was used to prevent spasm. Then, a ligature was tied around
the artery, and the catheter was tunneled subcutaneously to exit at the
back of the neck. The skin incision was closed with surgical staples.
Mice were allowed 3 hours to recover from the anesthesia and then were
placed in Plexiglas tubes to partially restrict their movements. Thirty
minutes later, the arterial line was connected to a pressure
transducer, and blood pressure and heart rate were recorded every 20
seconds for 15 minutes with a computerized data-acquisition
system.14
Blood and Tissue Samples
After blood pressure measurements, 300 µL of blood was drawn
through the arterial line into tubes containing EDTA. Plasma samples
were frozen in liquid nitrogen and stored at -20°C. Mice were killed
by neck dislocation under deep halothane anesthesia. The heart was
removed and weighed without the atria. The heart and kidneys were
stored at -70°C until further processing.
Histology
Cardiac weight index (CWI) was calculated as CWI=Heart Wet
Weight (mg)/Body Weight (g). In some experiments, the thoracic aortas
were collected and fixed in 4% formaldehyde. Aortic cross-sectional
area was determined as follows. Hematoxylin-eosin–stained sections
were analyzed with a laser-scanning confocal microscope (MRC 500
confocal imaging system, Bio-Rad) in the transmission mode. For each
vessel, four determinations of the outer (R) and inner (r) diameters
were obtained from two different sections. Since the heart and
vasculature were not fixed at a constant pressure, cross-sectional area
(CSA) was the only parameter determined and was calculated as
CSA=
(R2-r2).
Plasma Renin Concentrations
Plasma renin concentrations were measured with a modification of
a previously described microassay based on Ang I trapping by
antibody.15 Briefly, aliquots of plasma samples were
incubated for 15 minutes at 37°C in the presence of nephrectomized
rat plasma as a source of renin substrate and a predetermined amount of
a rabbit anti–Ang I polyclonal antiserum. The Ang I concentrations
produced during the incubation period were determined with a sensitive
radioimmunoassay.
Northern Blotting
Total RNA was purified from frozen tissues by the guanidine
thiocyanate/cesium chloride gradient technique as
described.16 Ten micrograms of total RNA was fractionated
by electrophoresis on a 1.2% formaldehyde–agarose gel and transferred
by capillarity on Hybond-N nitrocellulose membranes (Amersham). Kidney
RNAs were hybridized with an [-32P]dCTP randomly
labeled mouse renin probe (a kind gift of Dr K. Nakayama, University of
Tsukuba [Japan]) for 12 hours at 42°C in the presence of 50%
formamide. The intensity of the hybridization signals was quantified
with an Instant Imager detector (Packard Instruments). The blot was
then stripped and hybridized again with a mouse ß-actin cDNA probe.
Hybridization signals were similarly analyzed, and results are
expressed as the ratio of the renin to the ß-actin signal. A similar
procedure was applied to RNAs extracted from cardiac tissues. These
RNAs were hybridized successively to radiolabeled mouse ANP and GAPDH
probes. The results are presented as the ratio of the ANP to the GAPDH
signal.
Reverse Transcription–Polymerase Chain Reaction
One microgram total RNA was reversed transcribed into cDNA, and
-skeletal actin expression was detected by polymerase chain reaction
(PCR) amplification with a set of primers, named SKAC/F1 (forward) and
SKAC/B1 (backward), specific to the 3' untranslated region of the
-skeletal actin RNA. Coamplification of the GAPDH RNA was carried
out with the specific primers MGAP/F3 (forward) and MGAP/B1 (backward).
One amplification cycle included denaturation at 95°C and annealing
at 60°C for 1 minute each. A total of 20 cycles was performed.
Preliminary experiments demonstrated linearity between signal intensity
and the amount of total RNA present in the samples with the use of this
number of cycles. A final 10-minute extension period at 72°C was also
included. PCR products were separated on a 6% polyacrylamide gel.
Since the reaction mixture contained [-32P]dCTP, it
allowed quantitative analysis of the PCR products by means of an
Instant Imager detector. Results are expressed as the ratio of the
radioactivity associated with the -skeletal actin–specific band to
the GAPDH signal. The oligonucleotide sequences are as follows:
SKAC/F1: 5'-TCTCTCCTCAGGACGACAATCGAC-3'; SKAC/B1:
5'-CCTTTCCACAGGGCTTTGTTTG-3'; MGAP/F3: 5'-TGTTCCAGTATGACTCCACTCACGG-3';
and MGAP/B1: 5'-AGCCCTTCCACAATGCCAAAG-3'.
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Results |
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Determination of Clip Size Shown to Induce Hypertension
To determine the precise clip opening that would reduce renal perfusion and induce high blood pressure without producing renal infarction, we evaluated clips with lumen sizes ranging from 0.04 to 0.18 mm in the 2K1C model. Preliminary experiments demonstrated that sizes of 0.10 mm and smaller always resulted in renal infarction of the clipped kidney, whereas sizes of 0.13 mm and larger did not cause any kidney damage but were not able to induce hypertension (data not shown). Since high blood pressure was observed in most of the mice carrying clips with 0.11- or 0.12-mm openings, we initiated a second series of experiments to investigate the development of high blood pressure induced by these clips (Table 1
).
The main difference between the two sizes consisted of the higher
incidence of renal infarction in mice bearing the 0.11-mm clip than in
those bearing the 0.12-mm clip. It is noteworthy that blood pressure
was not elevated in mice with signs of infarction.
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We then evaluated the effects of these two clip sizes on the blood
pressure of uninephrectomized mice (1K1C model). Similar to what we
observed in the 2K1C model, hypertension developed rapidly with 0.12-mm
clips (Table 2). Mice demonstrated an identical number
of renal infarctions in this model. However, renal ischemia was
lethal in this case because of the absence of a normal contralateral
kidney. This was particularly evident in the group of mice bearing
0.11-mm clips in which most of the mice died 1 week after clipping.
Tables 1
and 2 also show intra-arterial blood pressures in sham and
clipped mice at different times after clipping. In the 2K1C model with
0.12-mm clips, a significant rise in blood pressure was observed 2
weeks after surgery, with no further increase at 4 weeks. In contrast,
clipping of the artery in uninephrectomized mice not only resulted in
an elevated blood pressure 2 weeks after surgery but the values
continued to rise until 4 weeks. At 4 weeks, blood pressure in 1K1C
mice was also considerably higher than observed in 2K1C mice. Heart
rate appeared slightly increased in the 2K1C group, whereas it remained
unchanged in the 1K1C model. Since the 0.12-mm clip was demonstrated to
be the most suitable for our study, we used it to further characterize
the two models in the experiments described below.
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Renin Expression in the Kidneys and Plasma Renin
Concentration
Because the 2K1C and 1K1C models differ in their dependence on an
activated renin-angiotensin system during the chronic phase of
hypertension, we measured renin expression in the kidneys of clipped
mice as a means to evaluate renin synthesis. As expected, renin mRNA
levels in the clipped kidney of 2K1C mice were greatly elevated
compared with those measured both in the contralateral normal kidney
and in kidneys from sham-operated mice (Fig 1A). On the
other hand, no activation of renin expression could be detected in
clipped kidneys from uninephrectomized mice (Fig 1B). Plasma renin
concentrations were also measured 4 weeks after clipping. Fig 2 demonstrates that plasma renin levels in 2K1C mice
were significantly higher than those observed in control mice. In
accordance with what was seen at the RNA level, plasma renin
concentrations in 1K1C mice were not different from basal values.
Plasma renin activity was also determined in these mice and found to be
exactly correlated with the levels of circulating renin (data not
shown).
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Cardiovascular Hypertrophy and Cardiac -Skeletal Actin and ANP
Expression in Heart
To estimate the increase in cardiac mass, we calculated the
cardiac weight index in 2K1C and 1K1C mice. The 1K1C mice demonstrated
a remarkable development of cardiac hypertrophy, whereas only a modest,
but still significant, increase in cardiac weight index was observed in
2K1C mice (Tables 1 and 2). Absolute heart weight followed the same
pattern (data not shown). In both models, cardiac growth appeared
maximal already 2 weeks after clipping. Expression of the -skeletal
actin gene, which is known to be activated during the development of
cardiac hypertrophy, was also determined (Fig 3). In
2K1C mice, -skeletal actin gene expression in the heart did not
appear to be different from that observed in control mice, whereas
expression was strongly activated in 1K1C mice (Fig 3B). Similarly, ANP
expression was highly increased in ventricles from 1K1C mice and was
not significantly different from control values in 2K1C mice (Fig 4). To determine whether vascular hypertrophy was also
present in 2K1C and 1K1C mice, we measured the cross-sectional area of
the thoracic aortas. Fig 5 demonstrates a significant
increase in the aortic cross-sectional area in both models of
hypertension.
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Discussion |
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With the advances of transgenesis and targeted gene disruption, the mouse has become more important as an animal model for cardiovascular research.3 17 18 These new technologies have created a need for methods for evaluation of the physiology of genetically modified animals. In the early 1930s, Goldblatt described a model of renovascular hypertension in dogs, and later, Miksche et al19 established the 2K1C and 1K1C models in the rat. These models were used extensively for a better understanding of the relationship among the renin-angiotensin system, hypertension, and cardiovascular disorders.20 The present study describes the development of the 2K1C and 1K1C models in the mouse.
Irrespective of species, the 2K1C model is characterized by an increase in blood pressure immediately after clipping, which parallels the release of active renin in the bloodstream.21 For several weeks thereafter, the degree of hypertension correlates with plasma renin concentration. Although the present report describes the mouse model at only two points in its course, our data suggest that the murine model shares the same features as those in other species. To minimize variability, we used solid stainless steel clips to constrict the left renal artery. The size of the clip opening was critical by a hundredth of a millimeter in order to induce hypertension without renal infarction. This is in contrast to rats, in which different levels of hypertension can be obtained depending on the dimension of the clip opening.21 In the mouse, resistance to renin-dependent high blood pressure after acute renin infusion has been observed.22 23 Since plasma angiotensinogen concentrations are rate limiting in the renin reaction, the lack of blood pressure response to renin infusion has been partially attributed to the relatively low substrate concentrations measured in the mouse.23 Our study demonstrates that chronic renin-dependent hypertension can develop in mice. Whether this requires the long-term activation of angiotensinogen synthesis to restore plasma levels remains to be established.
In the rat, the 1K1C model is characterized by a more rapid and higher rise in blood pressure than in the 2K1C model. Our experiments in mice confirm the same distinction between the two models of hypertension known from rat models. Dietary sodium content and clip size were the same in both mouse groups. Renin secretion, measured 4 weeks after surgery, was not stimulated in 1K1C mice, in agreement with what we know from other species,21 in which there is no activation of the renin-angiotensin system in the chronic stages of 1K1C hypertension.
Sustained hypertension causes the myocardium to adapt to an increased
load. The adaptive response is characterized by an overall increased
protein synthesis, which results eventually in increased cardiac
mass.24 Indeed, cardiac hypertrophy has been observed in a
murine model of pressure overload following constriction of the aortic
arch.25 A hypertrophic heart is also a characteristic
feature of the two Goldblatt models in different
species,10 26 and the present study extends these findings
to the mouse. Cardiac hypertrophy is characterized by the expression of
protein isoforms that are normally not expressed in the adult
heart.8 Along this line, the transcript for -skeletal
muscle actin accumulates in the heart after pressure
overload.8 27 Our data show that cardiac hypertrophy is
readily demonstrated in 1K1C mice (Table 2) and that -skeletal actin
and ANP expression are activated in the hearts of these mice (Figs 3 and 4). The accumulation of -skeletal actin appears higher 2 weeks
after clipping than 2 weeks later. This is in accordance with what was
found in a rat model of pressure overload,27 in which
-skeletal actin accumulation was maximal at the beginning of the
hypertrophic process and then gradually decreased. In 2K1C mice, the
development of cardiac hypertrophy is not as pronounced, and the
accumulation of -skeletal actin and ANP does not seem to be
different from that found in control animals. Since blood pressure is
higher in 1K1C than 2K1C mice, it is likely that the activation of
these genes depends primarily on the extent of hypertension. Vascular
hypertrophy was present in both 2K1C and 1K1C mice. Histological
examination of the blood vessels in hypertensive humans and in a
variety of animal models of hypertension clearly demonstrates an
association between high blood pressure and structural changes in the
vascular bed.28
In conclusion, from the available evidence, the single renin gene mouse does not behave differently from the rat in the 2K1C and 1K1C models of renovascular hypertension. Cardiovascular hypertrophy usually found in these models can be demonstrated in the mouse. The established murine models of high- and low-renin hypertension represent useful tools for cardiovascular research, particularly for the study of transgenic animals.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported in part by a grant of the Swiss National Science Foundation. We are grateful to Christine Munoz for her excellent technical support. We wish to thank Dr Hans-R. Brunner for helpful suggestions and for critical reading of the manuscript.
Received July 31, 1996; first decision August 26, 1996; accepted October 14, 1996.
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L. Mazzolai, M. A. Duchosal, M. Korber, K. Bouzourene, J. F. Aubert, H. Hao, V. Vallet, H. R. Brunner, J. Nussberger, G. Gabbiani, et al. Endogenous Angiotensin II Induces Atherosclerotic Plaque Vulnerability and Elicits a Th1 Response in ApoE-/- Mice Hypertension, September 1, 2004; 44(3): 277 - 282. [Abstract] [Full Text] [PDF]
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O. Jung, S. L. Marklund, H. Geiger, T. Pedrazzini, R. Busse, and R. P. Brandes Extracellular Superoxide Dismutase Is a Major Determinant of Nitric Oxide Bioavailability: In Vivo and Ex Vivo Evidence From ecSOD-Deficient Mice Circ. Res., October 3, 2003; 93(7): 622 - 629. [Abstract] [Full Text] [PDF]
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L. Cervenka, V. Horacek, I. Vaneckova, J. A. Hubacek, M. I. Oliverio, T. M. Coffman, and L. G. Navar Essential Role of AT1A Receptor in the Development of 2K1C Hypertension Hypertension, November 1, 2002; 40(5): 735 - 741. [Abstract] [Full Text] [PDF]
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H. Duplain, R. Burcelin, C. Sartori, S. Cook, M. Egli, M. Lepori, P. Vollenweider, T. Pedrazzini, P. Nicod, B. Thorens, et al. Insulin Resistance, Hyperlipidemia, and Hypertension in Mice Lacking Endothelial Nitric Oxide SynthaseNote Added in Proof Circulation, July 17, 2001; 104(3): 342 - 345. [Abstract] [Full Text] [PDF]
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S. PRADERVAND, Q. WANG, M. BURNIER, F. BEERMANN, J. D. HORISBERGER, E. HUMMLER, and B. C. ROSSIER A Mouse Model for Liddle's Syndrome J. Am. Soc. Nephrol., December 1, 1999; 10(12): 2527 - 2533. [Abstract] [Full Text]
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X.-P. Yang, Y.-H. Liu, N.-E. Rhaleb, N. Kurihara, H. E. Kim, and O. A. Carretero Echocardiographic assessment of cardiac function in conscious and anesthetized mice Am J Physiol Heart Circ Physiol, November 1, 1999; 277(5): H1967 - H1974. [Abstract] [Full Text] [PDF]
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J.-A. Haefliger, P. Meda, A. Formenton, P. Wiesel, A. Zanchi, H. R. Brunner, P. Nicod, and D. Hayoz Aortic Connexin43 Is Decreased During Hypertension Induced by Inhibition of Nitric Oxide Synthase Arterioscler Thromb Vasc Biol, July 1, 1999; 19(7): 1615 - 1622. [Abstract] [Full Text] [PDF]
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P. Madeddu, A. F. Milia, M. B. Salis, L. Gaspa, W. Gross, A. Lippoldt, and C. Emanueli Renovascular Hypertension in Bradykinin B2-Receptor Knockout Mice Hypertension, September 1, 1998; 32(3): 503 - 509. [Abstract] [Full Text] [PDF]
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Y. M Pinto, M. Paul, and D. Ganten Lessons from rat models of hypertension: from Goldblatt to genetic engineering Cardiovasc Res, July 1, 1998; 39(1): 77 - 88. [Abstract] [Full Text] [PDF]
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L. Mazzolai, J. Nussberger, J.-F. Aubert, D. B. Brunner, G. Gabbiani, H. R. Brunner, and T. Pedrazzini Blood Pressure–Independent Cardiac Hypertrophy Induced by Locally Activated Renin-Angiotensin System Hypertension, June 1, 1998; 31(6): 1324 - 1330. [Abstract] [Full Text] [PDF]
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A. Cavalli, A.-L. Lattion, E. Hummler, M. Nenniger, T. Pedrazzini, J.-F. Aubert, M. C. Michel, M. Yang, G. Lembo, C. Vecchione, et al. Decreased blood pressure response in mice deficient of the alpha 1b-adrenergic receptor PNAS, October 14, 1997; 94(21): 11589 - 11594. [Abstract] [Full Text] [PDF]
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H. Tokuyama, K. Hayashi, H. Matsuda, E. Kubota, M. Honda, K. Okubo, Y. Ozawa, and T. Saruta Stenosis-dependent role of nitric oxide and prostaglandins in chronic renal ischemia Am J Physiol Renal Physiol, May 1, 2002; 282(5): F859 - F865. [Abstract] [Full Text] [PDF]
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P. Wiesel, A. P. Patel, I. M. Carvajal, Z. Y. Wang, A. Pellacani, K. Maemura, N. DiFonzo, H. G. Rennke, M. D. Layne, S.-F. Yet, et al. Exacerbation of Chronic Renovascular Hypertension and Acute Renal Failure in Heme Oxygenase-1-Deficient Mice Circ. Res., May 25, 2001; 88(10): 1088 - 1094. [Abstract] [Full Text] [PDF]
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