(Hypertension. 2000;35:800.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Heme Oxygenase-1 Is Upregulated in the Kidney of Angiotensin II–Induced Hypertensive Rats
Possible Role in Renoprotection
From the Department of Cardiovascular Medicine (T.A., N.I., J.-i.T., R.N., M.O.), University of Tokyo Graduate School of Medicine (Japan); Department of Pathology (I.M.), Tokai University School of Medicine, Kanagawa, Japan; and Pediatric Nephrology Laboratory (S.-S.T., J.R.I.), Massachusetts General Hospital, Boston, Mass.
Correspondence to Nobukazu Ishizaka, MD, PhD, Department of Cardiovascular Medicine, University of Tokyo, Graduate School of Medicine, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail nobuishizka-tky{at}umin.ac.jp
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Abstract |
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Abstract—In this study, we investigated the regulation and physiological role of heme oxygenase-1 (HO-1) in the kidney of rats with hypertension. Rats were continuously administered either angiotensin II (Ang II) or norepinephrine with an osmotic minipump for up to 7 days. Ang II infusion decreased the glomerular filtration rate (GFR) as determined through creatinine clearance (3.2±0.2 versus 1.2±0.2 mL/min with Ang II infusion, P<0.01) and increased proteinuria (9.7±1.3 versus 28.1±7.2 mg/d with Ang II infusion, P<0.01). In contrast, norepinephrine did not alter these laboratory values. Ang II infusion significantly increased HO-1 expression in mRNA (442±98% of control at day 5, P<0.01) and protein levels (314±49% of control at day 5, P<0.01). Immunohistochemistry showed that in the kidney of normotensive rats, HO-1 was expressed mainly in the basal side in the renal tubules. After Ang II infusion, HO-1 staining was more extensively dispersed in the tubular epithelial cells. The intraperitoneal administration of zinc protoporphyrin, an HO inhibitor, to Ang II–infused rats further decreased GFR (0.8±0.1 mL/min) and increased proteinuria (52.5±13.0 mg/d). In contrast, the administration of hemin, an HO inducer, ameliorated the Ang II–induced decrease in GFR (2.4±0.2 mL/min) and increase in proteinuria (9.3±4.5 mg/d). These data suggest that HO-1 upregulation in the kidney of Ang II–induced hypertensive rats may exert a renoprotective effect against Ang II–induced renal injury.
Key Words: hypertension • angiotensin II • proteinuria • oxidative stress • kidney
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Introduction |
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Hypertension induces structural and functional alterations in the kidney, eventually leading to end-stage renal disease. The control of blood pressure retards the progression of renal failure and reduces the morbidity and mortality rates associated with hypertensive vascular disease.1 2 Although several clinical trials have shown a similar slowing of the progression with the use of either ACE inhibitors or other antihypertensive drugs,3 the superiority of ACE inhibitors has been demonstrated in some studies. Compared with other classes of antihypertensive drugs, ACE inhibitors were more effective than other agents in preservation of the glomerular filtration rate4 and in their antiproteinuric effects5 6 in essential hypertension. The extra effectiveness of ACE inhibitors may derive from their ability to preferentially dilate the efferent arterioles7 and their antiproliferative effects.8
Heme oxygenase (HO) is a rate-limiting enzyme of heme catabolism that has 2 isoforms: HO-1, an inducible form,9 10 and HO-2, a constitutive form. Induced HO-1 is thought to act as an antioxidative and anti-inflammatory defense mechanism through the degradation of cellular heme (pro-oxidant) and increase in biliverdin (antioxidant11 ). The carbon monoxide (CO) that is produced also has physiological functions, such as vascular relaxation12 and inhibition of platelet aggregation,13 through the activation of soluble guanylyl cyclase. The recent findings that HO-1 gene transfer ameliorated oxidative tissue injury14 and that oxidant-induced cellular injury was increased in HO-1 knockout mice15 and in human HO-1 deficiency16 provide further direct evidence that HO-1 acts favorably against oxidative stress. In the kidney, both HO-1 and HO-2 are present in the tubular epithelial cells,17 18 suggesting that the HO system also plays a role in the kidney. In fact, HO-1 induction exerts a protective effect on renal function in animal models of rhabdomyolysis,19 cisplatin nephrotoxicity,20 and nephrotoxic nephritis.21 In previous reports, we demonstrated that HO-1 expression was regulated by Ang II in vascular smooth muscle in both pressor-dependent22 and pressor-independent23 manners.
Renal damage occurs via pressor-dependent and -independent mechanisms. The present study was designed to examine both such mechanisms in the angiotensin II (Ang II) model of hypertension in the rat. We first assessed the pressor-dependent and -independent effects of Ang II on renal function. We next examined the effect of Ang II on renal HO-1 expression. We also used immortalized rat proximal tubule cells (IRPTCs) to investigate the effect of Ang II on HO-1 expression in the proximal tubule in vitro.
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Methods |
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Animal Models
The rat Ang II hypertension model was induced in Sprague-Dawley rats (Nippon Bio-Supply Center) through the subcutaneous implantation of an osmotic minipump (model 2001; Alza) as described previously.22 Val5-Ang II (Sigma Chemical Co) was infused at a rate of 0.7 mg · kg-1 · d-1 for up to 7 days. Systolic and diastolic blood pressures and heart rate were measured in conscious rats with tail-cuff plethysmography (UR-5000; Ueda Seisakusyo). In some experiments, the selective Ang II type 1 (AT1) receptor antagonist losartan (25 mg · kg-1 · d-1; a kind gift from Dr R.D. Smith, Dupont/Merck) or the nonspecific vasodilator hydralazine (15 mg · kg-1 · d-1; Sigma Chemical Co) was administered in the drinking water, beginning 2 days before pump implantation and throughout the Ang II infusion. So we could examine another model of hypertension, norepinephrine (NE) was infused at a rate of 2.8 mg · kg-1 · d-1 with the same system through polyethylene tubing (Becton Dickinson) that was placed in the superior vena cava via the left external jugular vein.22
Some rats were subjected to a daily intraperitoneal injection of the HO-1 inducer hemin (50 µmol · kg-1 · d-1; Sigma Chemical Co) or the HO-1 inhibitor zinc-protoporphyrin (ZnPP) (50 µmol · kg-1 · d-1; Porphyrin Products), which was started 2 days before pump implantation and continued until sacrifice. In addition, some rats were subjected to a daily intraperitoneal injection of the same amount of hemin or ZnPP for 9 consecutive days without Ang II infusion.
Assay of Plasma and Urine Samples
A 24-hour urine sample was collected before sacrifice. Plasma
and urine creatinine concentrations were measured with the
Jaffe reaction, and urinary protein was measured with the pyrogallol
red–molybdate protein dye-binding method (SRL).
Culture of Transformed Rat Proximal Tubular Cells
Culture of established IRPTCs was performed as described
previously.24 Briefly, cells were cultured in DMEM with
5% FCS. Cultures were supplemented with 3.8 mg/mL
NaHCO3, 25 mmol/L HEPES buffer (pH 7.5),
0.1 mmol/L sodium pyruvate, 100 U/mL penicillin, 100 µg/mL
streptomycin, and 0.01 mmol/L nonessential amino acids. For the
Ang II stimulation, cells were cultured in DMEM supplemented with 0.1%
FCS for 48 hours before and throughout the stimulation.
RNA Isolation and Northern Blot Analysis
Total RNA was isolated from homogenized heart
according to the acid guanidinium thiocyanate–phenol–chloroform
method with Isogen (Wako Pure Chemicals). Rat HO-1 cDNA (a kind gift
from Dr S. Shibahara, Tohoku [Japan] University School of Medicine)
was labeled with 
-32P-dCTP (DuPont-New England
Nuclear) with commercial kits (Nippon Gene). Hybridization was
performed as described previously.23 Hybridized bands were
visualized and quantified with a bioimaging analyzer (BAS 2000;
Fuji Photo Film), and band density was normalized to the intensity of
ethidium bromide–stained 28S and 18S ribosomal RNAs.
Protein Purification and Western Blot Analysis
Protein was isolated through homogenization
of samples in the lysis buffer (50 mmol/L HEPES, 5 mmol/L
EDTA, and 50 mmol/L NaCl, pH 7.5) containing protease
inhibitors (10 µg/mL aprotinin, 1 mmol/L PMSF, and
10 µg/mL leupeptin). Antibodies against rat HO-1 and rat HO-2
(StressGen) were used at a 1:1000 dilution, and horseradish
peroxidase–conjugated secondary antibody (Jackson
ImmunoResearch) was used at a 1:2000 dilution. The ECL Western blotting
system (Amersham Life Sciences) was used for detection. Bands were
visualized with a luminoanalyzer (LAS-1000; Fuji Photo Film).
Band intensity was calculated with Image software (NIH, Research
Service Branch) and expressed as a percentage of control.
Immunohistochemistry
Immunohistochemistry of HO-1 was performed as described
previously.25 Briefly, deparaffinized sections were
preincubated with 10% horse serum. Sections were then incubated with
the anti–HO-1 antibody at a 1:200 dilution at 37°C for 1 hour.
Slides were washed and incubated with biotinylated secondary antibody.
After treatment of the slides with Elite ABC kit (Vector Laboratories),
antigens were visualized with the 3,3-diaminobenzidine
tetrahydrochloride (DAKO) system. Counterstaining was performed with
methyl green (DAKO).
Assay of HO Activity
Biliverdin reductase was crudely purified according to the
method of Tenhunen et al.26 The assay of HO activity was
performed as described previously.23
Statistical Analysis
Data are expressed as mean±SEM with ANOVA, followed by a
multiple comparisons test for comparisons of initial data before
expression as a percentage of the control. A value of
P<0.05 was considered to be statistically significant.
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Results |
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Time Course of Systolic and Diastolic Blood Pressures and Heart Rate
The infusion of either Ang II and NE increased blood pressure and heart rate to similar extents (Table 1). Both hydralazine and losartan normalized Ang II–induced hypertension at day 7. The Ang II–induced increase in heart rate was completely normalized with losartan but only partially normalized with hydralazine (Table 1). Treatment with either hydralazine or losartan alone had no significant effect on blood pressure or heart rate (data not shown).
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Effect of Ang II and NE on Renal Function and Proteinuria
An infusion of Ang II at the dosage of 0.7 mg ·
kg-1 · d-1 for 7
consecutive days resulted in a significant decrease in the
glomerular filtration rate (GFR) determined through
creatinine clearance (Table 2). Ang II also increased proteinuria to
3 times the control level. All of these laboratory values returned
to normal levels after the administration of the specific
AT1 receptor blocker losartan. The
nonspecific vasodilator hydralazine also normalized proteinuria
but did not reverse the Ang II–induced decrease in GFR. In rats
receiving either a subpressor dose of Ang II (0.25 mg ·
kg-1 · d-1) or NE,
neither GFR nor the degree of proteinuria was different from that in
normotensive rats.
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Effect of Ang II Infusion on HO-1 Expression in the Kidney
We then investigated HO-1 regulation in the kidney of rats with
Ang II–induced hypertension. HO-1 mRNA was significantly increased as
early as 1 day after Ang II infusion and increased further for up to 7
days (Figures 1A and 1B). This increase
in HO-1 mRNA expression was accompanied by an increase in HO-1 protein
(Figures 1C and 1D). HO activity in the microsomal fraction was
significantly elevated in the kidney of Ang II–infused rats compared
with the control animals (5.4±0.8 versus 2.9±0.4 nmol bilirubin
· mg-1 · h-1,
n=4, P<0.05).
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Effect of Vasodilators and NE on HO-1 Expression in the
Kidney
Both hydralazine and losartan completely blocked
the Ang II–induced HO-1 protein upregulation in the kidney (Figures 2A and 2B), which suggests that Ang
II–induced HO-1 upregulation is a pressor-dependent event. This notion
is supported by the fact that the subpressor dose of Ang II infusion
did not increase HO-1 protein expression (Figures 2C and 2D). In
contrast, however, NE infusion did not upregulate HO-1 at all (Figures 2C and 2D). These findings suggest that the presence of both
hypertension and high levels of circulating Ang II is necessary for the
upregulation of renal HO-1 expression. Ang II infusion did not alter
HO-2 expression in the kidney (Figure 2E). To examine whether
Ang II has a direct effect on tubular HO-1 expression, IRPTCs were
stimulated with 100 nmol/L Ang II. As shown in Figure 2F, Ang II
stimulation significantly increased the HO-1 expression in IRPTCs
(compared with control, 2 h 337±58% and 4 h 340±25%; n=4,
P<0.05.)
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HO-1 Immunohistochemistry
Immunohistochemistry of HO-1 revealed that HO-1 was present in
both proximal and distal tubules in the kidney of normotensive rats.
HO-1 staining in the tubular epithelial cells was more extensively
distributed after Ang II infusion (Figures 3A and 3B). Under higher magnification, a
distinct staining for HO-1 along the basal side of tubular epithelial
cells was evident, whereas the luminal side of these cells was poorly
stained in the kidney of normotensive rats (Figure 3C). In
contrast, HO-1 staining was more extensive and was seen throughout the
epithelial cells (Figure 3D) in the kidney of Ang II–infused
rats. HO-1 expression was also increased in the arterial
wall at the renal hilus in response to Ang II infusion (Figures 3E and 3F).
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Effects of Inducer and Inhibitor of HO on HO-1
Expression, Hemodynamics, Renal Function, and
Proteinuria
To investigate the possible
physiological relevance of Ang II–induced HO-1
upregulation in the kidney, either hemin or ZnPP was
intraperitoneally administered to rats. As
expected, hemin injection, but not ZnPP injection, upregulated renal
HO-1 protein expression in the kidney (Figure 4A). HO-1 was also markedly upregulated
by hemin injection in the other tested organs (Figure 4B).
Immunohistochemistry revealed that hemin-induced HO-1 upregulation in
the kidney was mainly seen in the tubular region (Figure 4C).
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Hemin injection slightly decreased blood pressure in control rats, although it was not statistically significant. In addition, hemin normalized the Ang II–induced blood pressure elevation (Table 3). In contrast, ZnPP did not affect blood pressure in either control rats or these receiving Ang II (Table 3). Hemin or ZnPP injection did not significantly change GFR or proteinuria in normotensive rats. However, hemin increased GFR and decreased proteinuria in Ang II–infused rats. On the contrary, ZnPP augmented the Ang II–induced decrease in GFR and increase in proteinuria (Table 3).
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Discussion |
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In the present study, we showed that the continuous infusion of a pressor dose of Ang II, but not NE, resulted in a decrease in GFR and an increase in proteinuria. After an infusion of Ang II, renal HO-1 mRNA, protein, and activity were significantly increased. Immunohistochemistry demonstrated that HO-1 was mainly present in the basal side of tubular epithelial cells in the kidney of normotensive rats but that HO-1 was more extensively expressed in these areas in the Ang II–infused rat. The administration of the HO inducer hemin ameliorated and the HO inhibitor ZnPP exacerbated renal injury induced by Ang II infusion, suggesting that HO-1 upregulation in the kidney of Ang II–infused rat may protect against Ang II–induced renal injury.
Our first observation was that Ang II infusion resulted in an increase in proteinuria and a decrease in GFR. The former was blocked by either losartan or hydralazine, but the latter was blocked only by losartan. Because NE infusion affected neither GFR nor proteinuria, it appears that in the Ang II–infused rat, AT1 receptor–mediated action of Ang II is responsible for the decreased GFR, whereas the synergistic action of Ang II and pressor overload is critical for the increased proteinuria.
We then found that HO-1 was upregulated in the kidney of rats rendered hypertensive with Ang II infusion but not in rats receiving the NE infusion. In addition, Ang II–induced HO-1 upregulation was blocked by either losartan or hydralazine. These data suggest that the synergistic action of circulating high levels of Ang II and pressor overload is critical for HO-1 upregulation. This pattern of HO-1 regulation in the kidney differs from that in the aorta, where HO-1 has been reported to be upregulated in response to hypertension per se.22 The precise mechanisms of HO-1 upregulation remain unknown. Other investigators have reported elevated intrarenal Ang II levels in the Ang II–infused rat.27 Because AT1 receptor is abundantly expressed in the proximal and distal tubules,28 it is possible that HO-1 upregulation was due to the direct effect of intraluminal Ang II. In the present study, the finding that HO-1 was upregulated by Ang II in vitro in IRPTCs, in which AT1 receptor is expressed,24 may support this hypothesis. It was of note that Ang II–induced HO-1 upregulation occurred in parallel with increased proteinuria. It has been reported that tubular protein overload upregulates proinflammatory mediators in the renal tubules.29 30 Therefore, it is possible that HO-1 was upregulated in response to increased proteinuria as an anti-inflammatory defense.
Occasionally, when HO-1 was upregulated, a 30-kDa immunoreactive band appeared on immunoblot analysis (Figures 1C, 2A, 2C, 4A, and 4B). Because that 30-kDa band emerged when HO-1 protein was markedly increased in IRPTCs with the infection of an adenoviral vector containing the rat HO-1 gene (N. Ishizaka, unpublished data, 1999), this band most likely is HO-1 protein that has undergone posttranslational modification or degradation.
The possible physiological importance of renal HO-1 upregulation in the Ang II–infused rat is 3-fold. First, like nitric oxide synthase,31 HO-1 may partially counteract the vasoconstrictor influence of elevated circulating Ang II via the CO-mediated activation of soluble guanylate cyclase. Second, HO may activate 70-pS potassium channel in the rat thick ascending limb32 via CO production. Potassium recycling via the activation of potassium channel plays an important role in the provision of an adequate supply of potassium to the Na+,K+,Cl- cotransporter. Therefore, Ang II may play a role in sodium reabsorption through the activation of potassium channel as well as the activation of the Na+,K+,Cl- cotransporter.33 Third, the induction of HO-1 may be an adaptive response that protects the kidney against renal insults. HO-1 induction exerts a renoprotective effect in animal models of rhabdomyolysis19 and nephrotoxic nephritis.21 In the present study, the administration of ZnPP to Ang II–infused rats further decreased GFR and increased proteinuria. In contrast, the administration of hemin to Ang II–infused rats ameliorated GFR decrease and lessened proteinuria. These findings support the hypothesis that Ang II–induced HO-1 upregulation in the kidney provides renoprotection. Because hemin administration completely suppressed Ang II–induced blood pressure elevation, its antiproteinuric effect may also be attributed to its antihypertensive effect, as in the case with hydralazine. This antihypertensive effect of hemin appears to be consistent with previous reports showing that hemin or HO substrates normalized blood pressure in other types of hypertension.34 35 The mechanisms of the antihypertensive effect of HO-1 upregulation may involve CO-mediated activation of soluble guanylate cyclase36 and the activation of calcium-activated potassium channels.37
In summary, the continuous infusion of Ang II induced a renal injury in both a pressor-independent (decreased GFR) and a pressor-dependent (proteinuria) manner. HO-1 was upregulated in the kidney of rats with Ang II–induced hypertension. The findings that HO-1 induction ameliorated and HO inhibition augmented Ang II–induced renal injury suggest that Ang II–induced upregulation of HO-1 may act renoprotectively against renal injury evoked by chronic Ang II infusion.
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Acknowledgments |
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We are highly appreciative of Noriko Ogura for her technical assistance and Drs Masaomi Nangaku and Kazuhisa Tsukamoto for their constructive comments.
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Footnotes |
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1 These authors contributed equally to this work.
Received August 24, 1999; first decision October 19, 1999; accepted October 26, 1999.
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References |
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S. R. Datla, G. J. Dusting, T. A. Mori, C. J. Taylor, K. D. Croft, and F. Jiang Induction of Heme Oxygenase-1 In Vivo Suppresses NADPH Oxidase Derived Oxidative Stress Hypertension, October 1, 2007; 50(4): 636 - 642. [Abstract] [Full Text] [PDF]
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 F. T. Botros and L. G. Navar Interaction between endogenously produced carbon monoxide and nitric oxide in regulation of renal afferent arterioles Am J Physiol Heart Circ Physiol, December 1, 2006; 291(6): H2772 - H2778. [Abstract] [Full Text] [PDF]
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Y. Tayem, T. R. Johnson, B. E. Mann, C. J. Green, and R. Motterlini Protection against cisplatin-induced nephrotoxicity by a carbon monoxide-releasing molecule Am J Physiol Renal Physiol, April 1, 2006; 290(4): F789 - F794. [Abstract] [Full Text] [PDF]
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 Y. Izuhara, M. Nangaku, R. Inagi, N. Tominaga, T. Aizawa, K. Kurokawa, C. van Ypersele de Strihou, and T. Miyata Renoprotective Properties of Angiotensin Receptor Blockers beyond Blood Pressure Lowering J. Am. Soc. Nephrol., December 1, 2005; 16(12): 3631 - 3641. [Abstract] [Full Text] [PDF]
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K. Saito, N. Ishizaka, M. Hara, G. Matsuzaki, M. Sata, I. Mori, M. Ohno, and R. Nagai Lipid Accumulation and Transforming Growth Factor-{beta} Upregulation in the Kidneys of Rats Administered Angiotensin II Hypertension, November 1, 2005; 46(5): 1180 - 1185. [Abstract] [Full Text] [PDF]
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S. Wesseling, D. A. Ishola Jr., J. A. Joles, H. A. Bluyssen, H. A. Koomans, and B. Braam Resistance to oxidative stress by chronic infusion of angiotensin II in mouse kidney is not mediated by the AT2 receptor Am J Physiol Renal Physiol, June 1, 2005; 288(6): F1191 - F1200. [Abstract] [Full Text] [PDF]
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A. Pflueger, A. J. Croatt, T. E. Peterson, L. A. Smith, L. V. d'Uscio, Z. S. Katusic, and K. A. Nath The hyperbilirubinemic Gunn rat is resistant to the pressor effects of angiotensin II Am J Physiol Renal Physiol, March 1, 2005; 288(3): F552 - F558. [Abstract] [Full Text] [PDF]
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P. Li, H. Jiang, L. Yang, S. Quan, S. Dinocca, F. Rodriguez, N. G. Abraham, and A. Nasjletti Angiotensin II induces carbon monoxide production in the perfused kidney: relationship to protein kinase C activation Am J Physiol Renal Physiol, November 1, 2004; 287(5): F914 - F920. [Abstract] [Full Text] [PDF]
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Y. Chen, A.-P. Arrigo, and R. W. Currie Heat shock treatment suppresses angiotensin II-induced activation of NF-{kappa}B pathway and heart inflammation: a role for IKK depletion by heat shock? Am J Physiol Heart Circ Physiol, September 1, 2004; 287(3): H1104 - H1114. [Abstract] [Full Text] [PDF]
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L. Yang, S. Quan, A. Nasjletti, M. Laniado-Schwartzman, and N. G. Abraham Heme Oxygenase-1 Gene Expression Modulates Angiotensin II-Induced Increase in Blood Pressure Hypertension, June 1, 2004; 43(6): 1221 - 1226. [Abstract] [Full Text] [PDF]
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F. K. Johnson, W. Durante, K. J. Peyton, and R. A. Johnson Heme oxygenase-mediated endothelial dysfunction in DOCA-salt, but not in spontaneously hypertensive, rat arterioles Am J Physiol Heart Circ Physiol, May 1, 2004; 286(5): H1681 - H1687. [Abstract] [Full Text] [PDF]
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B. Rodriguez-Iturbe, N. D. Vaziri, J. Herrera-Acosta, and R. J. Johnson Oxidative stress, renal infiltration of immune cells, and salt-sensitive hypertension: all for one and one for all Am J Physiol Renal Physiol, April 1, 2004; 286(4): F606 - F616. [Abstract] [Full Text] [PDF]
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J. A. Joles and H. A. Koomans Causes and Consequences of Increased Sympathetic Activity in Renal Disease Hypertension, April 1, 2004; 43(4): 699 - 706. [Abstract] [Full Text] [PDF]
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H. A. Koomans, P. J. Blankestijn, and J. A. Joles Sympathetic Hyperactivity in Chronic Renal Failure: A Wake-up Call J. Am. Soc. Nephrol., March 1, 2004; 15(3): 524 - 537. [Abstract] [Full Text] [PDF]
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E. M. Sikorski, T. Hock, N. Hill-Kapturczak, and A. Agarwal The story so far: molecular regulation of the heme oxygenase-1 gene in renal injury Am J Physiol Renal Physiol, March 1, 2004; 286(3): F425 - F441. [Abstract] [Full Text] [PDF]
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F. Rodriguez, B. D. Lamon, W. Gong, R. Kemp, and A. Nasjletti Nitric Oxide Synthesis Inhibition Promotes Renal Production of Carbon Monoxide Hypertension, February 1, 2004; 43(2): 347 - 351. [Abstract] [Full Text] [PDF]
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E. Ritz and V. Haxsen Angiotensin II and Oxidative Stress: An Unholy Alliance J. Am. Soc. Nephrol., November 1, 2003; 14(11): 2985 - 2987. [Full Text] [PDF]
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F. Rodriguez, F. Zhang, S. Dinocca, and A. Nasjletti Nitric oxide synthesis influences the renal vascular response to heme oxygenase inhibition Am J Physiol Renal Physiol, June 1, 2003; 284(6): F1255 - F1262. [Abstract] [Full Text] [PDF]
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Y.-H. Chen, S.-F. Yet, and M. A. Perrella Role of Heme Oxygenase-1 in the Regulation of Blood Pressure and Cardiac Function Experimental Biology and Medicine, May 1, 2003; 228(5): 447 - 453. [Abstract] [Full Text] [PDF]
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M. Bhaskaran, K. Reddy, N. Radhakrishanan, N. Franki, G. Ding, and P. C. Singhal Angiotensin II induces apoptosis in renal proximal tubular cells Am J Physiol Renal Physiol, May 1, 2003; 284(5): F955 - F965. [Abstract] [Full Text] [PDF]
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T. L. Pallone, Z. Zhang, and K. Rhinehart Physiology of the renal medullary microcirculation Am J Physiol Renal Physiol, February 1, 2003; 284(2): F253 - F266. [Abstract] [Full Text] [PDF]
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F. K. Johnson, W. Durante, K. J. Peyton, and R. A. Johnson Heme Oxygenase Inhibitor Restores Arteriolar Nitric Oxide Function in Dahl Rats Hypertension, January 1, 2003; 41(1): 149 - 155. [Abstract] [Full Text] [PDF]
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J. F. Ndisang, W. Zhao, and R. Wang Selective Regulation of Blood Pressure by Heme Oxygenase-1 in Hypertension Hypertension, September 1, 2002; 40(3): 315 - 321. [Abstract] [Full Text] [PDF]
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H. Mitani, N. Ishizaka, T. Aizawa, M. Ohno, S.-i. Usui, T. Suzuki, T. Amaki, I. Mori, Y. Nakamura, M. Sato, et al. In Vivo klotho Gene Transfer Ameliorates Angiotensin II-Induced Renal Damage Hypertension, April 1, 2002; 39(4): 838 - 843. [Abstract] [Full Text] [PDF]
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N. Ishizaka, T. Aizawa, M. Ohno, S.-i. Usui, I. Mori, S.-S. Tang, J. R. Ingelfinger, S. Kimura, and R. Nagai Regulation and Localization of HSP70 and HSP25 in the Kidney of Rats Undergoing Long-Term Administration of Angiotensin II Hypertension, January 1, 2002; 39(1): 122 - 128. [Abstract] [Full Text] [PDF]
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N. L. Jernigan, T. L. O'Donaughy, and B. R. Walker Correlation of HO-1 expression with onset and reversal of hypoxia-induced vasoconstrictor hyporeactivity Am J Physiol Heart Circ Physiol, July 1, 2001; 281(1): H298 - H307. [Abstract] [Full Text] [PDF]
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R. M. Touyz and E. L. Schiffrin Signal Transduction Mechanisms Mediating the Physiological and Pathophysiological Actions of Angiotensin II in Vascular Smooth Muscle Cells Pharmacol. Rev., December 1, 2000; 52(4): 639 - 672. [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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