This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Aizawa, T. Articles by Ohno, M. Search for Related Content PubMed PubMed Citation Articles by Aizawa, T. Articles by Ohno, M. Related Collections ACE/Angiotension receptors Animal models of human disease

(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

Toru Aizawa¹; Nobukazu Ishizaka¹; Jun-ichi Taguchi; Ryozo Nagai; Ichiro Mori; Shiow-Shih Tang; Julie R. Ingelfinger; Minoru Ohno

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

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
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

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
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 effects^{5 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.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
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.

	Results

Top Abstract Introduction Methods Results Discussion References

 
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).

View this table: [in this window] [in a new window]   Table 1. Hemodynamic Parameters in Ang–and NE-infused rats

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.

View this table: [in this window] [in a new window]   Table 2. Renal Function and Proteinuria After Ang II and NE Infusion

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).

View larger version (46K): [in this window] [in a new window]   Figure 1. Effect of continuous Ang II infusion on renal HO-1 expression. A and B, effect of Ang II infusion on HO-1 mRNA levels. A, representative Northern blot. B, summarized data from 4 to 6 Northern blots. C and D, effect of Ang II infusion on HO-1 protein levels. C, representative Western blot. In addition to a 32-kDa band, a 30-kDa band was occasionally detected. D, summarized data from 4 to 6 animals. *P<0.05 and **P<0.01 vs sham-operated control.

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.)

View larger version (40K): [in this window] [in a new window]   Figure 2. Effects of antihypertensive agents, subpressor doses of Ang II, and NE on renal HO-1 protein expression. A and B, effects of losartan (Los) and hydralazine (Hyd). Both drugs completely blocked Ang II–induced HO-1 upregulation. C and D, effects of subpressor doses of Ang II (0.25 mg · kg-1 · d-1) and NE. Regardless of its hypertensive effect, NE infusion did not increase renal HO-1 expression, as did Ang II. Ang II increased HO-1 expression at 0.7 mg · kg-1 · d-1 but not at 0.25 mg · kg-1 · d-1. A and C, representative immunoblots. B and D, summarized data from 4 to 6 animals. *P<0.01 vs sham-operated control. E, representative Western blot of HO-2 protein from 3 independent experiments. F, effect of Ang II in vitro on renal tubular cells. IRPTCs were stimulated by 100 nmol/L Ang II for indicated time.

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).

View larger version (126K): [in this window] [in a new window]   Figure 3. Localization of HO-1. HO-1 staining in kidney of normotensive rats (A, C, and E) and Ang II–induced hypertensive rats (B, D, and F). A and B, HO-1 staining in glomerular and tubular regions (magnification x40). C and D, higher-magnification microphotograph of HO-1 staining in tubular region. After Ang II infusion, HO-1 staining extended over a wider area to luminal side. E and F, microphotograph of HO-1 staining in renal artery at renal hilus (C to F magnification x100).

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).

View larger version (66K): [in this window] [in a new window]   Figure 4. Effect of HO-1 inducer hemin and HO-1 inhibitor ZnPP on renal HO-1 protein expression. A, effects of hemin and ZnPP on renal HO-1 expression. Left, representative immunoblots. Right, summarized data from 3 or 4 independent experiments (*P<0.05 and **P<0.01 compared with control, respectively). B, effects of hemin on HO-1 expression in other organs. Representative immunoblot of 2 independent experiments. C, immunohistochemistry of HO-1 in kidney of normotensive rats (left) and hemin-injected rats (right). Increased HO-1 staining was observed in tubular area in Ang II–infused rat kidney (*).

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).

View this table: [in this window] [in a new window]   Table 3. Effect of Hemin and ZnPP on Blood Pressure and Renal Function in Ang II–Infused Rats

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
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.

	Acknowledgments

 
We are highly appreciative of Noriko Ogura for her technical assistance and Drs Masaomi Nangaku and Kazuhisa Tsukamoto for their constructive comments.

	Footnotes

 
¹ These authors contributed equally to this work.

Received August 24, 1999; first decision October 19, 1999; accepted October 26, 1999.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Collins R, Peto R, MacMahon S, Hebert P, Fiebach NH, Eberlein KA, Godwin J, Qizilbash N, Taylor JO, Hennekens CH. Blood pressure, stroke, and coronary heart disease, part 2: short-term reductions in blood pressure: overview of randomised drug trials in their epidemiological context. Lancet. 1990;335:827–838.[Medline] [Order article via Infotrieve]
2. Rodicio JL. Does antihypertensive therapy protect the kidney in essential hypertension? J Hypertens Suppl. 1996;14:S69–S75; discussion S75–S76.[Medline] [Order article via Infotrieve]
3. Nielsen FS, Rossing P, Gall MA, Skott P, Smidt UM, Parving HH. Long-term effect of lisinopril and atenolol on kidney function in hypertensive NIDDM subjects with diabetic nephropathy. Diabetes. 1997;46:1182–1188.[Abstract]
4. Himmelmann A, Hansson L, Hansson BG, Hedstrand H, Skogstrom K, Ohrvik J, Furangen A. Long-term renal preservation in essential hypertension: angiotensin converting enzyme inhibition is superior to beta-blockade. Am J Hypertens. 1996;9:850–853.[Medline] [Order article via Infotrieve]
5. Ruilope LM, Lahera V, Alcazar JM, Praga M, Campo C, Rodicio JL. Randomly allocated study of the effects of standard therapy versus ACE inhibition on micro-albuminuria in essential hypertension. J Hypertens Suppl. 1994;12:S59–S63.[Medline] [Order article via Infotrieve]
6. Buzio C, Regolisti G, Perazzoli F, Mutti A, Bergamaschi E, Borghetti A. Renal effects of nifedipine and captopril in patients with essential hypertension and reduced renal reserve. Hypertension. 1994;24:763–769.[Abstract/Free Full Text]
7. Weidmann P, Schneider M, Bohlen L. Therapeutic efficacy of different antihypertensive drugs in human diabetic nephropathy: an updated meta-analysis. Nephrol Dial Transplant. 1995;10(suppl 9):39–45.
8. Amann K, Irzyniec T, Mall G, Ritz E. The effect of enalapril on glomerular growth and glomerular lesions after subtotal nephrectomy in the rat: a stereological analysis. J Hypertens. 1993;11:969–975.[Medline] [Order article via Infotrieve]
9. Vile GF, Tyrrell RM. Oxidative stress resulting from ultraviolet A irradiation of human skin fibroblasts leads to a heme oxygenase-dependent increase in ferritin. J Biol Chem. 1993;268:14678–14681.[Abstract/Free Full Text]
10. Foresti R, Clark JE, Green CJ, Motterlini R. Thiol compounds interact with nitric oxide in regulating heme oxygenase-1 induction in endothelial cells: involvement of superoxide and peroxynitrite anions. J Biol Chem. 1997;272:18411–18417.[Abstract/Free Full Text]
11. Stocker R, Yamamoto Y, McDonagh AF, Glazer AN, Ames BN. Bilirubin is an antioxidant of possible physiological importance. Science. 1987;235:1043–1046.[Abstract/Free Full Text]
12. Coceani F. Carbon monoxide and dilation of blood vessels. Science. 1993;260:739. Letter, comment.[Free Full Text]
13. Brune B, Ullrich V. Inhibition of platelet aggregation by carbon monoxide is mediated by activation of guanylate cyclase. Mol Pharmacol. 1987;32:497–504.[Abstract]
14. Otterbein LE, Kolls JK, Mantell LL, Cook JL, Alam J, Choi AM. Exogenous administration of heme oxygenase-1 by gene transfer provides protection against hyperoxia-induced lung injury. J Clin Invest. 1999;103:1047–1054.[Medline] [Order article via Infotrieve]
15. Poss KD, Tonegawa S. Reduced stress defense in heme oxygenase 1-deficient cells. Proc Natl Acad Sci U S A. 1997;94:10925–10930.[Abstract/Free Full Text]
16. Yachie A, Niida Y, Wada T, Igarashi N, Kaneda H, Toma T, Ohta K, Kasahara Y, Koizumi S. Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency. J Clin Invest. 1999;103:129–135.[Medline] [Order article via Infotrieve]
17. Agarwal A, Shiraishi F, Visner GA, Nick HS. Linoleyl hydroperoxide transcriptionally upregulates heme oxygenase-1 gene expression in human renal epithelial and aortic endothelial cells. J Am Soc Nephrol. 1998;9:1990–1997.[Abstract]
18. Hu Y, Ma N, Yang M, Semba R. Expression and distribution of heme oxygenase-2 mRNA and protein in rat kidney. J Histochem Cytochem. 1998;46:249–256.[Abstract/Free Full Text]
19. 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.
20. 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.[Medline] [Order article via Infotrieve]
21. Mosley K, Wembridge DE, Cattell V, Cook HT. Heme oxygenase is induced in nephrotoxic nephritis and hemin, a stimulator of heme oxygenase synthesis, ameliorates disease. Kidney Int. 1998;53:672–678.[Medline] [Order article via Infotrieve]
22. Ishizaka N, de Leon H, Laursen JB, Fukui T, Wilcox JN, De Keulenaer G, Griendling KK, Alexander RW. Angiotensin II–induced hypertension increases heme oxygenase-1 expression in rat aorta. Circulation. 1997;96:1923–1929.[Abstract/Free Full Text]
23. Ishizaka N, Griendling KK. Heme oxygenase-1 is regulated by angiotensin II in rat vascular smooth muscle cells. Hypertension. 1997;29:790–795.[Abstract/Free Full Text]
24. Ingelfinger JR, Jung F, Diamant D, Haveran L, Lee E, Brem A, Tang SS. Rat proximal tubule cell line transformed with origin-defective SV40 DNA: autocrine ANG II feedback. Am J Physiol. 1999;276:F218–F227.
25. Aizawa T, Ishizaka N, Taguchi J, Kimura S, Kurokawa K, Ohno M. Balloon injury does not induce heme oxygenase-1 expression, but administration of hemin inhibits neointimal formation in balloon-injured rat carotid artery. Biochem Biophys Res Commun. 1999;261:302–307.[Medline] [Order article via Infotrieve]
26. Tenhunen R, Marver HS, Schmid R. The enzymatic catabolism of hemoglobin: stimulation of microsomal heme oxygenase by hemin. J Lab Clin Med. 1970;75:410–421.[Medline] [Order article via Infotrieve]
27. Zou LX, Imig JD, von Thun AM, Hymel A, Ono H, Navar LG. Receptor-mediated intrarenal angiotensin II augmentation in angiotensin II–infused rats. Hypertension. 1996;28:669–677.[Abstract/Free Full Text]
28. Harrison-Bernard LM, Navar LG, Ho MM, Vinson GP, el-Dahr SS. Immunohistochemical localization of ANG II AT1 receptor in adult rat kidney using a monoclonal antibody. Am J Physiol. 1997;273:F170–F177.[Abstract/Free Full Text]
29. Wang Y, Chen J, Chen L, Tay YC, Rangan GK, Harris DC. Induction of monocyte chemoattractant protein-1 in proximal tubule cells by urinary protein. J Am Soc Nephrol. 1997;8:1537–1545.[Abstract]
30. Zoja C, Liu XH, Abbate M, Corna D, Schiffrin EL, Remuzzi G, Benigni A. Angiotensin II blockade limits tubular protein overreabsorption and the consequent upregulation of endothelin 1 gene in experimental membranous nephropathy. Exp Nephrol. 1998;6:121–131.[Medline] [Order article via Infotrieve]
31. Chin SY, Wang CT, Majid DS, Navar LG. Renoprotective effects of nitric oxide in angiotensin II-induced hypertension in the rat. Am J Physiol. 1998;274:F876–F882.
32. Liu H, Mount DB, Nasjletti A, Wang W. Carbon monoxide stimulates the apical 70-pS K⁺ channel of the rat thick ascending limb. J Clin Invest. 1999;103:963–970.[Medline] [Order article via Infotrieve]
33. Amlal H, LeGoff C, Vernimmen C, Soleimani M, Paillard M, Bichara M. ANG II controls Na⁺-K⁺(NH₄⁺)-2Cl^- cotransport via 20-HETE and PKC in medullary thick ascending limb. Am J Physiol. 1998;274:C1047–C1056.
34. 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.[Abstract/Free Full Text]
35. 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.
36. Furchgott RF, Jothianandan D. Endothelium-dependent and -independent vasodilation involving cyclic GMP: relaxation induced by nitric oxide, carbon monoxide and light. Blood Vessels. 1991;28:52–61.[Medline] [Order article via Infotrieve]
37. Wang R, Wu L. The chemical modification of K_Ca channels by carbon monoxide in vascular smooth muscle cells. J Biol Chem. 1997;272:8222–8226.[Abstract/Free Full Text]

This article has been cited by other articles:

				F. T. Botros, M. C. Prieto-Carrasquero, V. L. Martin, and L. G. Navar Heme oxygenase induction attenuates afferent arteriolar autoregulatory responses Am J Physiol Renal Physiol, October 1, 2008; 295(4): F904 - F911. [Abstract] [Full Text] [PDF]

				Y. Ren, M. A. D'Ambrosio, H. Wang, R. Liu, J. L. Garvin, and O. A. Carretero Heme oxygenase metabolites inhibit tubuloglomerular feedback (TGF) Am J Physiol Renal Physiol, October 1, 2008; 295(4): F1207 - F1212. [Abstract] [Full Text] [PDF]

				A. Kobayashi, K. Ishikawa, H. Matsumoto, S. Kimura, Y. Kamiyama, and Y. Maruyama Synergetic Antioxidant and Vasodilatory Action of Carbon Monoxide in Angiotensin II Induced Cardiac Hypertrophy Hypertension, December 1, 2007; 50(6): 1040 - 1048. [Abstract] [Full Text] [PDF]

				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]

				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]

				X. Liao, J.-M. Liu, L. Du, A. Tang, Y. Shang, S. Q. Wang, L.-Y. Chen, and Q. Chen Nitric oxide signaling in stretch-induced apoptosis of neonatal rat cardiomyocytes FASEB J, September 1, 2006; 20(11): 1883 - 1885. [Abstract] [Full Text] [PDF]

				S. W. Ryter, J. Alam, and A. M. K. Choi Heme Oxygenase-1/Carbon Monoxide: From Basic Science to Therapeutic Applications Physiol Rev, April 1, 2006; 86(2): 583 - 650. [Abstract] [Full Text] [PDF]

				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]

				L. Wu and R. Wang Carbon Monoxide: Endogenous Production, Physiological Functions, and Pharmacological Applications Pharmacol. Rev., December 1, 2005; 57(4): 585 - 630. [Abstract] [Full Text] [PDF]

				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]

				N. Ishizaka, K. Saito, I. Mori, G. Matsuzaki, M. Ohno, and R. Nagai Iron Chelation Suppresses Ferritin Upregulation and Attenuates Vascular Dysfunction in the Aorta of Angiotensin II-Infused Rats Arterioscler. Thromb. Vasc. Biol., November 1, 2005; 25(11): 2282 - 2288. [Abstract] [Full Text] [PDF]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

E. Ritz and V. Haxsen Angiotensin II and Oxidative Stress: An Unholy Alliance J. Am. Soc. Nephrol., November 1, 2003; 14(11): 2985 - 2987.