Skip to main content
  • American Heart Association
  • Science Volunteer
  • Warning Signs
  • Advanced Search
  • Donate

  • Home
  • About this Journal
    • General Statistics
    • Editorial Board
    • Editors
    • Information for Advertisers
    • Author Reprints
    • Commercial Reprints
    • Customer Service and Ordering Information
  • All Issues
  • Subjects
    • All Subjects
    • Arrhythmia and Electrophysiology
    • Basic, Translational, and Clinical Research
    • Critical Care and Resuscitation
    • Epidemiology, Lifestyle, and Prevention
    • Genetics
    • Heart Failure and Cardiac Disease
    • Hypertension
    • Imaging and Diagnostic Testing
    • Intervention, Surgery, Transplantation
    • Quality and Outcomes
    • Stroke
    • Vascular Disease
  • Browse Features
    • AHA Guidelines and Statements
    • Acknowledgment of Reviewers
    • Clinical Implications
    • Clinical-Pathological Conferences
    • Controversies in Hypertension
    • Editors' Picks
    • Guidelines Debate
    • Meeting Abstracts
    • Recent Advances in Hypertension
    • SPRINT Trial: the Conversation Continues
  • Resources
    • Instructions to Reviewers
    • Instructions for Authors
    • →Article Types
    • → Submission Guidelines
      • Research Guidelines
        • Minimum Information About Microarray Data Experiments (MIAME)
      • Abstract
      • Acknowledgments
      • Clinical Implications (Only by invitation)
      • Conflict(s) of Interest/Disclosure(s) Statement
      • Figure Legends
      • Figures
      • Novelty and Significance: 1) What Is New, 2) What Is Relevant?
      • References
      • Sources of Funding
      • Tables
      • Text
      • Title Page
      • Online/Data Supplement
    • →Tips for Easier Manuscript Submission
    • → General Instructions for Revised Manuscripts
      • Change of Authorship Form
    • → Costs to Authors
    • → Open Access, Repositories, & Author Rights Q&A
    • Permissions to Reprint Figures and Tables
    • Journal Policies
    • Scientific Councils
    • AHA Journals RSS Feeds
    • International Users
    • AHA Newsroom
  • AHA Journals
    • AHA Journals Home
    • Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB)
    • Circulation
    • → Circ: Arrhythmia and Electrophysiology
    • → Circ: Genomic and Precision Medicine
    • → Circ: Cardiovascular Imaging
    • → Circ: Cardiovascular Interventions
    • → Circ: Cardiovascular Quality & Outcomes
    • → Circ: Heart Failure
    • Circulation Research
    • Hypertension
    • Stroke
    • Journal of the American Heart Association
  • Facebook
  • Twitter

  • My alerts
  • Sign In
  • Join

  • Advanced search

Header Publisher Menu

  • American Heart Association
  • Science Volunteer
  • Warning Signs
  • Advanced Search
  • Donate

Hypertension

  • My alerts
  • Sign In
  • Join

  • Facebook
  • Twitter
  • Home
  • About this Journal
    • General Statistics
    • Editorial Board
    • Editors
    • Information for Advertisers
    • Author Reprints
    • Commercial Reprints
    • Customer Service and Ordering Information
  • All Issues
  • Subjects
    • All Subjects
    • Arrhythmia and Electrophysiology
    • Basic, Translational, and Clinical Research
    • Critical Care and Resuscitation
    • Epidemiology, Lifestyle, and Prevention
    • Genetics
    • Heart Failure and Cardiac Disease
    • Hypertension
    • Imaging and Diagnostic Testing
    • Intervention, Surgery, Transplantation
    • Quality and Outcomes
    • Stroke
    • Vascular Disease
  • Browse Features
    • AHA Guidelines and Statements
    • Acknowledgment of Reviewers
    • Clinical Implications
    • Clinical-Pathological Conferences
    • Controversies in Hypertension
    • Editors' Picks
    • Guidelines Debate
    • Meeting Abstracts
    • Recent Advances in Hypertension
    • SPRINT Trial: the Conversation Continues
  • Resources
    • Instructions to Reviewers
    • Instructions for Authors
    • →Article Types
    • → Submission Guidelines
    • →Tips for Easier Manuscript Submission
    • → General Instructions for Revised Manuscripts
    • → Costs to Authors
    • → Open Access, Repositories, & Author Rights Q&A
    • Permissions to Reprint Figures and Tables
    • Journal Policies
    • Scientific Councils
    • AHA Journals RSS Feeds
    • International Users
    • AHA Newsroom
  • AHA Journals
    • AHA Journals Home
    • Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB)
    • Circulation
    • → Circ: Arrhythmia and Electrophysiology
    • → Circ: Genomic and Precision Medicine
    • → Circ: Cardiovascular Imaging
    • → Circ: Cardiovascular Interventions
    • → Circ: Cardiovascular Quality & Outcomes
    • → Circ: Heart Failure
    • Circulation Research
    • Hypertension
    • Stroke
    • Journal of the American Heart Association
Part 2 Original Articles

Tumor Necrosis Factor α Blockade Increases Renal Cyp2c23 Expression and Slows the Progression of Renal Damage in Salt-Sensitive Hypertension

Ahmed A. Elmarakby, Jeffrey E. Quigley, David M. Pollock, John D. Imig
Download PDF
https://doi.org/10.1161/01.HYP.0000198545.01860.90
Hypertension. 2006;47:557-562
Originally published February 16, 2006
Ahmed A. Elmarakby
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jeffrey E. Quigley
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
David M. Pollock
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
John D. Imig
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Tables
  • Info & Metrics
  • eLetters

Jump to

  • Article
    • Abstract
    • Methods
    • Results
    • Discussion
    • Acknowledgments
    • References
  • Figures & Tables
  • Info & Metrics
  • eLetters
Loading

Abstract

We hypothesized that the downregulation of Cyp2c by tumor necrosis factor (TNF) α contributes to hypertension and renal injury in salt-sensitive angiotensin hypertension. Male Sprague-Dawley rats were fed a high-salt diet (8% NaCl), and osmotic minipumps were implanted to deliver angiotensin II for 14 days. Rats were divided into 3 groups: high salt, angiotensin high salt, and angiotensin high salt administered the TNF-α blocker, etanercept. Arterial pressure increased from 94±5 to 148±7 mm Hg during week 1 in the angiotensin high-salt group, whereas etanercept slowed blood pressure elevation during the first week in the treated group (90±2 to 109±6 mm Hg). After 2 weeks, arterial pressure increased to 156±11 mm Hg in the angiotensin high-salt group and 141±6 mm Hg in the etanercept-treated group. Albuminuria and proteinuria were significantly elevated in angiotensin high-salt rats and were reduced in the etanercept-treated rats. Urinary monocyte chemoattractant protein-1 excretion significantly increased in the angiotensin high-salt group (275±47 versus 81±19 ng/day) and was decreased in the etanercept-treated group (153±31 ng/day). Angiotensin high-salt rats also had a significant increase in renal monocyte/macrophage infiltration, and this was again attenuated by etanercept treatment. Renal expression of Cyp2c23 decreased, whereas renal epoxide hydrolase expression increased in angiotensin high-salt rats. Etanercept treatment increased Cyp2c23 expression and lowered epoxide hydrolase expression. These data suggest that TNF-α contributes to downregulation of Cyp2c23, blood pressure regulation, and renal injury in angiotensin high-salt hypertension.

  • sodium, dietary
  • angiotensin
  • tumor necrosis factor
  • blood pressure
  • proteinuria
  • metabolism

Previous studies have shown that the renin–angiotensin system is important in the regulation of blood pressure, aldosterone release, and sodium reabsorption.1 Angiotensin II (Ang II) is a potent proinflammatory agent and mediates inflammatory cell chemotaxis and proliferation.2–4 Studies have also demonstrated that Ang II activation of the angiotensin type 1 receptor (AT1) results in an increase in the inflammatory cytokine tumor necrosis factor (TNF) α in a rat model of unilateral ureteral obstruction.5 Ang II also regulates the activation of nuclear factor κB and stimulates the production of chemokines, such as monocyte chemoattractant protein-1 (MCP-1), and cytokines, such as interleukin 6 and interleukin 8.4,6,7 Thus, Ang II is not only an important component in the regulation of blood pressure but is also involved in the inflammation that accompanies hypertension.

Epoxyeicosatrienoic acids (EETs) have been shown to contribute to vascular tone and improve endothelial function.8 In the Ang II model of salt-sensitive hypertension, renal EET production is inappropriately decreased. Cyp2c enzymes are the major EET-forming enzymes in the kidney,9 and EET production can be altered by changes in the expression and activity of these enzymes. Therefore, the downregulation of Cyp2c enzymes and any subsequent decrease in metabolites may limit any renal and cardiovascular protective effects of EETs. In addition to decreased epoxygenase output, the renal vasodilatory effects of EETs are also diminished when they are hydrated by soluble epoxide hydrolase (sEH) to dihydroxyeicosatrienoic acids.10 Recent reports have demonstrated a significant role for sEH in the long-term regulation of arterial blood pressure and inflammation.11–13

Epoxygenase metabolite and cytokine interactions have been demonstrated previously. However, a link to end-stage renal disease has not yet been well established. Cytokines have been shown to decrease cytochrome P450 expression in the liver and extrahepatic tissue.14,15 In endothelial cells, cytokines have also been shown to downregulate Cyp2c, as well as to reduce EET-mediated relaxation.16 Conversely, EETs are antiinflammatory in nature and possess the ability to inhibit TNF-α–elicited expression of vascular cell adhesion molecule 1 and to suppress cytokine activation.17 Nevertheless, a direct relationship between Cyp2c and TNF-α has not been completely elucidated. In the present study, we hypothesized that TNF-α is involved in the downregulation of the Cyp2c23 thereby reducing EET availability and contributing to blood pressure elevation and glomerular injury in Ang II salt-sensitive hypertension.

Methods

Animal protocols were approved by the Medical College of Georgia Animal Care and Use Committee. Male Sprague-Dawley rats were anesthetized with sodium pentobarbital (50 mg/kg IP) and implanted with radiotelemetry transmitters (Data Sciences, Inc) according to the manufacturer’s specifications.18 After steady basal blood pressure recording, rats were again anesthetized with sodium pentobarbital (50 mg/kg IP) and implanted with osmotic minipumps that were used to deliver Ang II at a dose of 65 ng/min for 14 days. All of the rats (n=27) were fed an 8% NaCl diet (HS) throughout the experiment and were divided into 3 groups: HS, ANG/HS, and ANG/HS treated with the soluble TNF-α receptor, etanercept (1.25 mg/kg per day via SC osmotic minipump for 2 weeks, Immunex Corp). Rats were placed in metabolic cages to facilitate 24-hour urine collection at the end of the experiment.

Biochemical Assays

Urinary protein excretion was determined with a standard Bradford assay.19 Urinary MCP-1 and albumin excretion were measured using commercially available immunoassay kits (BD Biosciences and Exocell, Inc, respectively).

Vascular Homogenization for Protein Preparations

Renal microvessels were dissected quickly in ice-cold homogenization buffer in the presence of protease inhibitors and frozen in liquid nitrogen for determination of Cyp2c23 and sEH protein expression using Western blotting as described previously.9 The primary antibodies used were Cyp2c23 rabbit anti-rat Cyp2c23 (1:5000; Dr. Capdevila, Vanderbilt University, Nashville, TN) and rabbit anti-mouse sEH (1:2000; Dr. Hammock, University of California at Davis, Davis, CA), respectively. Goat anti-rabbit IgG-horseradish peroxidase was used as a secondary antibody for Cyp2c23 (1:100 000) and sEH (1:40 000). Band intensity was measured densitometrically, and the values were normalized to β-actin.

Isolation of Glomeruli for Real-Time PCR

Glomeruli were isolated from rat kidneys by a modified procedure as described previously.20 Total RNA was isolated from glomeruli using ultra-pure Trizol reagent according to the procedure described by the manufacturer (GIBCO-BRL). Concentration of total RNA was determined by measuring absorbance at 260 nm. A blend of oligonucleotide and random hexanucleotide primers were used for the RT of equal amounts of total RNA (2 μg) using the iScript cDNA synthesis kit in accordance with the manufacturer’s instructions (Bio-Rad Laboratories). Oligonucleotide primer pairs and TaqMan probes were designed from the published cDNA sequences of Cyp2c23, sEH, and GAPDH using Beacon Designer software (Premier Biosoft International). GAPDH was used as an internal standard, and TaqMan real-time RT-PCR was used to quantify mRNA expression relative to a control. The amplification was performed using iQ Supermix with the iCycler iQ Real-Time Detection System according to the manufacturer’s instructions (Bio-Rad Laboratories). A standard curve was generated for each primer pair and probe set for the purpose of determining PCR efficiency. Each sample was run in triplicate, and the mean threshold cycle was used to calculate relative mRNA expression using the comparative mean threshold cycle method. TaqMan probes were dual labeled with a 5′ fluorophore and a 3′ quencher and sequences were used as follows: Cyp2c23 probe 5′-AGG CAC CGA GAC AAC CAG CAC CAC-3′; Cyp2c23 forward 5′-TGG CTG TCT GTG GGT CTA ACT-3′; Cyp2c23 reverse 5′-AAT CAC ACG GTC AAG TTC CTC AT-3′; sEH probe 5′-TTC CAC ACC AGC ACA CCA GCC CAG-3′; sEH forward 5′-CAG AAT AAA CTG GGA ATC CCT CAA-3′; sEH reverse 5′-CTC ACT CTC TCA GGG TGG AAG-3′; GAPDH probe 5′-ACT CCA CGA CAT ACT CAG CAC CAG CA-3′; GAPDH forward 5′-CAC GGC AAG TTC AAC GGC-3′; and GAPDH reverse 5′-GGT GGT GAA GAC GCC AGT A-3′.

Evaluation of Kidney Monocyte Infiltration

In a separate group of animals, kidneys were isolated, perfused with 10% formalin solution to fix the kidney tissue, and cut into sections for immunohistochemistry as described previously.21 Kidney slices were incubated with a primary antibody that recognizes monocytes/macrophages (mouse anti-rat CD68). Sections were then incubated with anti-mouse secondary conjugated to horseradish peroxidase and visualized using diaminobenzamine chromogen. CD68-positive cells were counted in cortex and medulla by an evaluator who had no knowledge of the treatment groups.

Statistical Analysis

All of the data are presented as mean±SEM. Between-group comparisons were made using 1-way ANOVA for randomized samples in conjunction with Tukey’s post hoc test to identify significant difference between groups. Differences were considered significant at P<0.05. The mRNA and protein expression data were analyzed by unpaired t test. Analyses were performed using GraphPad Prism Version 4.0 software.

Results

ANG/HS treatment significantly increased mean arterial pressure (MAP) compared with rats fed an HS diet. Etanercept began to lower MAP on day 4 of Ang II infusion and significantly attenuated the increase in MAP from day 6 through day 11 (Figure 1A). Afterward, from day 12 through day 14, MAP was not different between the ANG/HS and etanercept-treated group. Heart rate was initially reduced, apparently because of the increase in MAP, but then began to increase after day 9 of Ang II infusion (Figure 1B). The initial decrease in heart rate was identical in ANG/HS rats and ANG/HS rats given etanercept treatment. However, heart rate in the etanercept group was not restored to the same level as that of the ANG/HS group.

Figure1
  • Download figure
  • Open in new tab
  • Download powerpoint

Figure 1. Average 12 hours MAP (A) and heart rate (B) in ANG/HS rats with or without etanercept treatment for 2 weeks. Values are means±SE (n=5 per group).

Proteinuria after 2 weeks of Ang II infusion was used as an indicator of renal damage (Figure 2A). Urinary protein excretion was 5-fold higher in ANG/HS hypertensive rats than in control HS rats. This increase was significantly attenuated with etanercept treatment. Albuminuria was also used as an indicator of kidney damage (Figure 2B). Similar to protein excretion, urinary albumin excretion was elevated 80-fold in ANG/HS hypertensive rats compared with HS controls, and etanercept lowered urinary albumin excretion in ANG/HS rats.

Figure2
  • Download figure
  • Open in new tab
  • Download powerpoint

Figure 2. Urinary protein excretion (A) and albumin excretion (B) in ANG/HS rats with or without etanercept treatment for 2 weeks (n=9 animals per group). Values are means±SE. *P<0.05 vs HS and †P<0.05 vs ANG/HS.

Monocyte/macrophage infiltration was determined and used as an indicator of inflammation in the kidney. ANG/HS hypertensive rats showed a significant increase in CD68-positive staining, and etanercept treatment lowered macrophage infiltration in ANG/HS rats (Figure 3B). Urinary MCP-1 excretion was increased 3-fold in ANG/HS hypertensive rats compared with HS rats. Etanercept treatment also reduced MCP-1 excretion in ANG/HS hypertensive rats (Figure 3A).

Figure3
  • Download figure
  • Open in new tab
  • Download powerpoint

Figure 3. (A) Urinary MCP-1 excretion in HS rats and ANG/HS rats with or without etanercept treatment (n=9). (B) Average number of CD68 positive cells (monocytes/macrophages) per 1 mm2 in the kidney (cortex and medulla) of HS and ANG/HS rats with or without etanercept treatment (n=4 per group). Values are means±SE. *P<0.05 vs HS and †P<0.05 vs ANG/HS. (C) Representative image of monocyte/macrophage staining in the glomeruli of HS and ANG/HS rats with or without etanercept treatment.

Glomerular Cyp2c23 mRNA expression was decreased in ANG/HS hypertensive rats compared with HS rats (ANG/HS: 0.48±0.1 versus HS: 1.11±0.27 comparative Ct [2ďdCt]). Etanercept treatment increased Cyp2c23 mRNA expression to levels similar to HS rats (0.84±0.2 2ďdCt). We also detected an &6-fold increase in glomerular sEH mRNA expression in ANG/HS hypertensive rats compared with HS rats, and, in this case, etanercept treatment lowered sEH mRNA expression (ANG/HS: 10±5 versus HS: 1.7±0.8 versus ANG/HS/etanercept: 3.4±1.4 2ďdCt). Consistent with the glomerular mRNA expression data, Western blot analysis revealed a significant decrease in renal microvascular Cyp2c23 and an increase in sEH protein expression in ANG/HS rats when compared with rats on the HS diet alone (Figure 4). Etanercept treatment prevented the decrease in Cyp2c23 and the increase in sEH protein levels produced by ANG/HS.

Figure4
  • Download figure
  • Open in new tab
  • Download powerpoint

Figure 4. Renal microvascular Cyp2c23 (A) and sEH (B) protein expression normalized to β-actin expression in ANG/HS rats with or without etanercept treatment (n=9 per group). Values are means±SE. *P<0.05 vs HS and †P<0.05 vs ANG/HS.

Discussion

Recent studies suggest that inflammation is a key component in the pathogenesis of hypertension and cardiovascular disease. Therefore, targeting the inflammatory response may be a valuable strategy for lowering the incidence of hypertension and subsequent cardiovascular complications. In the present study, we examined the role of TNF-α in salt-sensitive Ang II hypertension. TNF-α blockade slowed the progression of hypertension and renal damage as evidenced by reduced urinary albumin and protein excretion. Blocking TNF-α also reduced urinary MCP-1 excretion and renal macrophage infiltration in ANG/HS rats. Furthermore, mRNA and protein expression of the epoxygenase Cyp2c23 decreased, whereas sEH mRNA and protein expression increased in hypertensive rats, presumably lowering EET bioavailability. TNF-α blockade resulted in increased Cyp2c23 and decreased sEH in ANG/HS. Together, these data suggest that TNF-α plays a central inflammatory role in the pathogenesis of salt-sensitive hypertension and its associated renal damage.

In agreement with our previously published data,8,18 Ang II infusion in rats fed a high-salt diet significantly increased blood pressure and urinary albumin and protein excretion. Etanercept treatment reduced urinary excretion of albumin and protein in ANG/HS rats. This result was consistent with the findings of Muller et al22 in which etanercept treatment attenuated albuminuria in double-transgenic rats harboring both human renin and angiotensinogen. Muller et al22 measured tail-cuff systolic blood pressure at the end of the etanercept treatment period and reported that the decrease in albuminuria was independent of blood pressure. In the present study, we continuously measured blood pressure by telemetry throughout the etanercept treatment period and found that etanerecept slowed the elevation of blood pressure. This blood pressure–reducing effect was not maintained to the end of the treatment period. Thus, the data in the present study provide evidence that etanercept treatment protects the kidney from damage, and this effect could be, at least in part, because of the ability of etanercept to slow the onset of hypertension.

Aside from promoting the inflammatory response, TNF-α has a broad spectrum of biological activity including vasodilation, increased vascular permeability, and platelet activation.23 Etanercept binds to TNF-α and prevents it from interacting with TNF-α receptors.24 Thus, blocking TNF-α may prove useful in reducing the incidence of cardiovascular diseases associated with hypertension. Studies have also shown that Ang II is capable of inducing inflammation through both blood pressure–dependent and –independent mechanisms and may be partly responsible for vascular inflammation associated with hypertension.25 Additionally, Ang II receptor blockers have been shown to prevent Ang II-induced vascular inflammation in a high-renin model of hypertension.25–27 One of the important aspects of inflammation is macrophage infiltration, which is normally a defense mechanism against bacterial infection. Vascular tissues, however, can sustain damage from inflammation and the resulting macrophage infiltration.27 Ang II augments the production of the inflammatory cytokines and chemokines.27 MCP-1 is a chemokine involved in the recruitment of monocytes during inflammation and is induced in vascular endothelial and smooth muscle cells in response to Ang II.28 In the present study, we found increased macrophage infiltration in the kidney of ANG/HS rats and a corresponding rise in protein, albumin, and MCP-1 excretion. By blocking TNF-α, macrophage infiltration and urinary MCP-1 excretion in ANG/HS were reduced along with markers of kidney damage. These data suggest that TNF-α is involved in the inflammatory response and renal damage in ANG/HS hypertension.

To explore the mechanisms by which etanercept reduced blood pressure, renal damage, and inflammation in salt-sensitive ANG hypertension, we examined the expression of enzymes that regulate EET levels in the glomeruli and renal microvessels of ANG/HS-treated rats. We found that Ang II infusion with an HS diet elicited a decrease in glomerular Cyp2c23 mRNA expression and an increase in sEH mRNA expression, whereas etanercept treatment corrected these changes. Western blotting revealed comparable changes in protein expression of Cyp2c23 and sEH in the renal microvessels of ANG/HS rats, again with reversal of these trends by etanercept treatment. Downregulation of renal CYP450 epoxygenase enzymes has been shown to be associated with hypertension and end-organ damage in double-transgenic rats and Ang II hypertension.18,29 In particular, Cyp2c23 is highly expressed in rat kidney, where it contributes to renal EET biosynthesis.9 EETs are involved in the regulation of vascular tone and have been shown to possess antiinflammatory, antiproliferative, antimigratory, and antithrombotic properties.10 A connection between inflammatory cytokines and Cyp2c enzymes has been established. Cytokines have been shown to downregulate Cyp2c enzymes and reduce EET-mediated relaxation.16 Node et al30 demonstrated that 11,12-EET inhibited TNF-α–elicited expression of vascular cell adhesion molecule 1 and activation of nuclear factor κB suggesting that EETs possess antiinflammatory properties in addition to their vasodilatory actions. Regulation of EETs by the sEH enzyme also contributes to vascular and inflammatory responses.10 Our laboratory has shown previously that sEH inhibition attenuates afferent arteriolar constriction to Ang II in hypertension.13 sEH inhibition also lowered blood pressure and ameliorated renal damage associated with Ang II hypertension.13 A recent study has demonstrated that sEH inhibitors decreased plasma levels of proinflammatory cytokines in lipopolysaccharide-treated mice.31 Collectively, the data in the present study suggest that the downregulation of Cyp2c23 and the increase in sEH expression are likely to be associated with the activation of TNF-α signaling in ANG/HS hypertension.

Perspectives

In conclusion, our data indicate that TNF-α is involved in the progression of hypertension and renal damage in salt-sensitive Ang II hypertension, and these effects may be, in part, attributed to decreased EET bioavailability through the downregulation of Cyp2c23 and the upregulation of sEH. In ANG/HS hypertensive rats, we observed that etanercept slowed the progression of hypertension and decreased renal damage. These results demonstrate a clear association between inflammation and the development of hypertension. Overall, these results suggest that reduction of the TNF-α–mediated inflammatory response may be a potential therapeutic strategy for treatment of hypertension and related end-organ dysfunction. Future studies will be needed to determine the specific mechanisms by which TNF-α regulates epoxygenase enzymes in salt-sensitive hypertension.

Acknowledgments

We express our appreciation for the expert technical assistance provided by Hiram Ocasio, Eric Merkley, Janet Hobbs, and Laura Townsend. These studies were supported by grants from the National Heart Lung and Blood Institute (HL59699 and HL074167), American Heart Association Established Investigator Awards (to J.D.I. and D.M.P.) and postdoctoral fellowships from Georgia National Kidney Foundation and Southeast Affiliate of the American Heart Association (to A.A.E.).

  • Received September 30, 2005.
  • Revision received October 26, 2005.
  • Accepted November 22, 2005.

References

  1. ↵
    Cowley AW Jr, Roman RJ. The role of the kidney in hypertension. JAMA. 1996; 275: 1581–1589.
    OpenUrlCrossRefPubMed
  2. ↵
    Ruiz-Ortega M, Lorenzo O, Suzuki Y, Ruperez M, Egido J. Proinflammatory actions of angiotensins. Curr Opin Nephrol Hypertens. 2001; 10: 321–329.
    OpenUrlCrossRefPubMed
  3. ↵
    Ruiz-Ortega M, Lorenzo O, Ruperez M, Esteban V, Mezzano S, Egido J. Renin-angiotensin system and renal damage: emerging data on angiotensin II as a proinflammatory mediator. Contrib Nephrol. 2001; 135: 123–137.
    OpenUrlPubMed
  4. ↵
    Hilgers KF, Hartner A, Porst M, Veelken R, Mann JF. Angiotensin II type 1 receptor blockade prevents lethal malignant hypertension: relation to kidney inflammation. Circulation. 2001; 104: 1436–1440.
    OpenUrlAbstract/FREE Full Text
  5. ↵
    Guo G, Morrissey J, McCracken R, Tolley T, Liapis H, Klahr S. Contributions of angiotensin II and tumor necrosis factor-alpha to the development of renal fibrosis. Am J Physiol Renal Physiol. 2001; 280: F777–F785.
    OpenUrlAbstract/FREE Full Text
  6. ↵
    Mezzano SA, Ruiz-Ortega M, Egido J. Angiotensin II and renal fibrosis. Hypertension. 2001; 38: 635–638.
    OpenUrlAbstract/FREE Full Text
  7. ↵
    Ruiz-Ortega M, Lorenzo O, Ruperez M, Suzuki Y, Egido J Angiotensin II activates nuclear transcription factor-kappaB in aorta of normal rats and in vascular smooth muscle cells of AT1 knockout mice. Nephrol Dial Transplant. 2001; 16 (Suppl 1): 27–33.
    OpenUrlAbstract/FREE Full Text
  8. ↵
    Zhao X, Pollock DM, Inscho EW, Zeldin DC, Imig JD. Decreased renal cytochrome P450 C enzymes and impaired vasodilation are associated with angiotensin salt-sensitive hypertension. Hypertension. 2003; 41: 709–714.
    OpenUrlAbstract/FREE Full Text
  9. ↵
    Zhao X, Pollock DM, Zeldin DC, Imig JD. Salt-sensitive hypertension after exposure to angiotensin is associated with inability to upregulate renal epoxygenases. Hypertension. 2003; 42: 775–780.
    OpenUrlAbstract/FREE Full Text
  10. ↵
    Imig JD. Epoxide hydrolase and epoxygenase metabolites as therapeutic targets for renal diseases. Am J Physiol Renal Physiol. 2005; 289: F496–F503.
    OpenUrlAbstract/FREE Full Text
  11. ↵
    Imig JD, Zhao X, Capdevila JH, Morisseau C, Hammock BD. Soluble epoxide hydrolase inhibition lowers arterial blood pressure in angiotensin II hypertension. Hypertension. 2002; 39: 690–694.
    OpenUrlAbstract/FREE Full Text
  12. ↵
    Yu Z, Xu F, Huse LM, Morisseau C, Draper AJ, Newman JW, Parker C, Graham L, Engler MM, Hammock BD, Zeldin DC, Kroetz DL. Soluble epoxide hydrolase regulates hydrolysis of vasoactive epoxyeicosatrienoic acids. Circ Res. 24 2000; 87: 992–998.
    OpenUrlAbstract/FREE Full Text
  13. ↵
    Zhao X, Yamamoto T, Newman JW, Kim IH, Watanabe T, Hammock BD, Stewart J, Pollock JS, Pollock DM, Imig JD. Soluble epoxide hydrolase inhibition protects the kidney from hypertension-induced damage. J Am Soc Nephrol. 2004; 15: 1244–1253.
    OpenUrlAbstract/FREE Full Text
  14. ↵
    Iber H, Chen Q, Cheng PY, Morgan ET. Suppression of CYP2C11 gene transcription by interleukin-1 mediated by NF-kappaB binding at the transcription start site. Arch Biochem Biophys. 2000; 377: 187–194.
    OpenUrlCrossRefPubMed
  15. ↵
    Siewert E, Bort R, Kluge R, Heinrich PC, Castell J, Jover R. Hepatic cytochrome P450 down-regulation during aseptic inflammation in the mouse is interleukin 6 dependent. Hepatology. 2000; 32: 49–55.
    OpenUrlCrossRefPubMed
  16. ↵
    Kessler P, Popp R, Busse R, Schini-Kerth VB. Proinflammatory mediators chronically downregulate the formation of the endothelium-derived hyperpolarizing factor in arteries via a nitric oxide/cyclic GMP-dependent mechanism. Circulation. 1999; 99: 1878–1884.
    OpenUrlAbstract/FREE Full Text
  17. ↵
    Node K, Ruan XL, Dai J, Yang SX, Graham L, Zeldin DC, Liao JK. Activation of Galpha s mediates induction of tissue-type plasminogen activator gene transcription by epoxyeicosatrienoic acids. J Biol Chem. 2001; 276: 15983–15989.
    OpenUrlAbstract/FREE Full Text
  18. ↵
    Sasser JM, Pollock JS, Pollock DM. Renal endothelin in chronic angiotensin II hypertension. Am J Physiol Regul Integr Comp Physiol. 2002; 283: R243–R248.
    OpenUrlAbstract/FREE Full Text
  19. ↵
    Elmarakby AA, Dabbs Loomis E, Pollock JS, Pollock DM. ETA receptor blockade attenuates hypertension and decreases reactive oxygen species in ETB receptor-deficient rats. J Cardiovasc Pharmacol. 2004; 44: S7–S10.
    OpenUrlCrossRefPubMed
  20. ↵
    Dey A, Williams RS, Pollock DM, Stepp DW, Newman JW, Hammock BD, Imig JD. Altered kidney CYP2C and cyclooxygenase-2 levels are associated with obesity-related albuminuria. Obes Res. 2004; 12: 1278–1289.
    OpenUrlCrossRefPubMed
  21. ↵
    Dey A, Maric C, Kaesemeyer WH, Zaharis CZ, Stewart J, Pollock JS, Imig JD. Rofecoxib decreases renal injury in obese Zucker rats. Clin Sci (Lond). 2004; 107: 561–570.
    OpenUrlPubMed
  22. ↵
    Muller DN, Shagdarsuren E, Park JK, Dechend R, Mervaala E, Hampich F, Fiebeler A, Ju X, Finckenberg P, Theuer J, Viedt C, Kreuzer J, Heidecke H, Haller H, Zenke M, Luft FC. Immunosuppressive treatment protects against angiotensin II-induced renal damage. Am J Pathol. 2002; 161: 1679–1693.
    OpenUrlCrossRefPubMed
  23. ↵
    Rennard SI. Antiinflammatory therapies other than corticosteroids. Proc Am Thorac Soc. 2004; 1: 282–287.
    OpenUrlCrossRefPubMed
  24. ↵
    Goffe B, Cather JC. Etanercept: An overview. J Am Acad Dermatol Aug. 2003; 49 (2 Suppl): S105–S111.
    OpenUrl
  25. ↵
    Mervaala E, Muller DN, Schmidt F, Park JK, Gross V, Bader M, Breu V, Ganten D, Haller H, Luft FC. Blood pressure-independent effects in rats with human renin and angiotensinogen genes. Hypertension. 2000; 35: 587–594.
    OpenUrlAbstract/FREE Full Text
  26. ↵
    Cheng ZJ, Finckenberg P, Louhelainen M, Merasto S, Tikkanen I, Vapaatalo H, Mervaala EM. Cardiovascular and renal effects of cyclooxygenase inhibition in transgenic rats harboring mouse renin-2 gene (TGR[mREN2]27). Eur J Pharmacol. 2003: 461; 159–169.
    OpenUrlCrossRefPubMed
  27. ↵
    Cheng ZJ, Vapaatalo H, Mervaala E. Angiotensin II and vascular inflammation. Med Sci Monit. 2005; 11: RA194–RA205.
    OpenUrlPubMed
  28. ↵
    Chen XL, Tummala PE, Olbrych MT, Alexander RW, Medford RM. Angiotensin II induces monocyte chemoattractant protein-1 gene expression in rat vascular smooth muscle cells. Circ Res. 1998; 83: 952–959.
    OpenUrlAbstract/FREE Full Text
  29. ↵
    Muller DN, Theuer J, Shagdarsuren E, Kaergel E, Honeck H, Park JK, Markovic M, Barbosa-Sicard E, Dechend R, Wellner M, Kirsch T, Fiebeler A, Rothe M, Haller H, Luft FC, Schunck WH. A peroxisome proliferator-activated receptor-alpha activator induces renal CYP2C23 activity and protects from angiotensin II-induced renal injury. Am J Pathol. 2004; 164: 521–532.
    OpenUrlPubMed
  30. ↵
    Node K, Huo Y, Ruan X, Yang B, Spiecker M, Ley K, Zeldin DC, Liao JK. Anti-inflammatory properties of cytochrome P450 epoxygenase-derived eicosanoids. Science. 1999; 285: 1276–1279.
    OpenUrlAbstract/FREE Full Text
  31. ↵
    Schmelzer KR, Kubala L, Newman JW, Kim IH, Eiserich JP, Hammock BD. Soluble epoxide hydrolase is a therapeutic target for acute inflammation. Proc Natl Acad Sci U S A. 2005; 102: 9772–9777.
    OpenUrlAbstract/FREE Full Text
View Abstract
Back to top
Previous ArticleNext Article

This Issue

Hypertension
March 2006, Volume 47, Issue 3
  • Table of Contents
Previous ArticleNext Article

Jump to

  • Article
    • Abstract
    • Methods
    • Results
    • Discussion
    • Acknowledgments
    • References
  • Figures & Tables
  • Info & Metrics
  • eLetters

Article Tools

  • Print
  • Citation Tools
    Tumor Necrosis Factor α Blockade Increases Renal Cyp2c23 Expression and Slows the Progression of Renal Damage in Salt-Sensitive Hypertension
    Ahmed A. Elmarakby, Jeffrey E. Quigley, David M. Pollock and John D. Imig
    Hypertension. 2006;47:557-562, originally published February 16, 2006
    https://doi.org/10.1161/01.HYP.0000198545.01860.90

    Citation Manager Formats

    • BibTeX
    • Bookends
    • EasyBib
    • EndNote (tagged)
    • EndNote 8 (xml)
    • Medlars
    • Mendeley
    • Papers
    • RefWorks Tagged
    • Ref Manager
    • RIS
    • Zotero
  •  Download Powerpoint
  • Article Alerts
    Log in to Email Alerts with your email address.
  • Save to my folders

Share this Article

  • Email

    Thank you for your interest in spreading the word on Hypertension.

    NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

    Enter multiple addresses on separate lines or separate them with commas.
    Tumor Necrosis Factor α Blockade Increases Renal Cyp2c23 Expression and Slows the Progression of Renal Damage in Salt-Sensitive Hypertension
    (Your Name) has sent you a message from Hypertension
    (Your Name) thought you would like to see the Hypertension web site.
  • Share on Social Media
    Tumor Necrosis Factor α Blockade Increases Renal Cyp2c23 Expression and Slows the Progression of Renal Damage in Salt-Sensitive Hypertension
    Ahmed A. Elmarakby, Jeffrey E. Quigley, David M. Pollock and John D. Imig
    Hypertension. 2006;47:557-562, originally published February 16, 2006
    https://doi.org/10.1161/01.HYP.0000198545.01860.90
    del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo

Related Articles

Cited By...

Subjects

  • Cardiology
    • Etiology
      • Hypertension
        • Hypertension
  • Vascular Disease
    • Peripheral Vascular Disease
  • Basic, Translational, and Clinical Research
    • Metabolism
    • Animal Models of Human Disease

Hypertension

  • About Hypertension
  • Instructions for Authors
  • AHA CME
  • Guidelines and Statements
  • Permissions
  • Journal Policies
  • Email Alerts
  • Open Access Information
  • AHA Journals RSS
  • AHA Newsroom

Editorial Office Address:
7272 Greenville Ave.
Dallas, TX 75231
email: hypertension@heart.org

Information for:
  • Advertisers
  • Subscribers
  • Subscriber Help
  • Institutions / Librarians
  • Institutional Subscriptions FAQ
  • International Users
American Heart Association Learn and Live
National Center
7272 Greenville Ave.
Dallas, TX 75231

Customer Service

  • 1-800-AHA-USA-1
  • 1-800-242-8721
  • Local Info
  • Contact Us

About Us

Our mission is to build healthier lives, free of cardiovascular diseases and stroke. That single purpose drives all we do. The need for our work is beyond question. Find Out More about the American Heart Association

  • Careers
  • SHOP
  • Latest Heart and Stroke News
  • AHA/ASA Media Newsroom

Our Sites

  • American Heart Association
  • American Stroke Association
  • For Professionals
  • More Sites

Take Action

  • Advocate
  • Donate
  • Planned Giving
  • Volunteer

Online Communities

  • AFib Support
  • Garden Community
  • Patient Support Network
  • Professional Online Network

Follow Us:

  • Follow Circulation on Twitter
  • Visit Circulation on Facebook
  • Follow Circulation on Google Plus
  • Follow Circulation on Instagram
  • Follow Circulation on Pinterest
  • Follow Circulation on YouTube
  • Rss Feeds
  • Privacy Policy
  • Copyright
  • Ethics Policy
  • Conflict of Interest Policy
  • Linking Policy
  • Diversity
  • Careers

©2018 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited. The American Heart Association is a qualified 501(c)(3) tax-exempt organization.
*Red Dress™ DHHS, Go Red™ AHA; National Wear Red Day ® is a registered trademark.

  • PUTTING PATIENTS FIRST National Health Council Standards of Excellence Certification Program
  • BBB Accredited Charity
  • Comodo Secured