(Hypertension. 2000;35:193.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
NF-
B Inhibition Ameliorates Angiotensin II–Induced Inflammatory Damage in Rats
From the Franz Volhard Clinic, Medical Faculty of the Charité, Berlin, Germany (D.N.M., R.D., J.-K.P., F.S., A.F., J.T., H.H., F.C.L.); Humboldt University of Berlin, Germany; Institute of Biomedicine, University of Helsinki, Finland (E.M.A.M.); Max Delbrück Center for Molecular Medicine, Berlin, Germany (D.G.); and F. Hoffmann-La Roche, Basel, Switzerland (V.B.). Dominik Müller, Ralf Dechend, and Eero Mervaala contributed equally to this work.
Correspondence to Friedrich C. Luft, Franz Volhard Clinic, Wiltberg Strasse 50, 13125 Berlin, Germany. E-mail luft{at}fvk-berlin.de
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionNF-{kappa}B Plays a Central...References |
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Abstract—We recently reported that the activation of nuclear factor-
B (NF-B) promotes inflammation in rats harboring both human renin and angiotensinogen genes (double-transgenic rats [dTGR]). We tested the hypothesis that the antioxidant pyrrolidine dithiocarbamate (PDTC) inhibits NF-B and ameliorates renal and cardiac end-organ damage. dTGR feature hypertension, severe renal and cardiac damage, and a 40% mortality rate at 7 weeks. Electrophoretic mobility shift assay showed increased NF-B DNA binding activity in hearts and kidneys of dTGR. Chronic PDTC (200 mg/kg SC) treatment decreased blood pressure (162±8 versus 190±7 mm Hg; P=0.02) in dTGR compared with dTGR controls. The cardiac hypertrophy index was also significantly reduced (4.90±0.1 versus 5.77±0.1 mg/g; P<0.001). PDTC reduced 24-hour albuminuria by >95% (2.5±0.8 versus 57.1±8.7 mg/d; P<0.001) and prevented death. Vascular injury was ameliorated in small renal and cardiac vessels. Electrophoretic mobility shift assay showed that PDTC inhibited NF-B binding activity in heart and kidney, whereas AP-1 activity in the kidney was not decreased. dTGR exhibited increased left ventricular c-fos and c-jun mRNA expression. PDTC treatment reduced c-fos but not c-jun mRNA. Immunohistochemistry showed increased p65 NF-B subunit expression in the endothelium and smooth muscle cells of damaged small vessels, as well as infiltrating cells in glomeruli, tubules, and collecting ducts of dTGR. PDTC markedly reduced the immunoreactivity of p65. PDTC also prevented the NF-B–dependent transactivation of the intercellular adhesion molecule ICAM-1 and inducible nitric oxide synthase. Monocyte infiltration was markedly increased in dTGR kidneys and hearts. Chronic treatment reduced monocyte/macrophage infiltration by 72% and 64%, respectively. Thus, these results demonstrate that PDTC inhibits NF-B activity, ameliorates inflammation, and protects against angiotensin II-induced end-organ damage.
Key Words: proteins • angiotensin II • inflammatory response • nitric oxide synthase • cell adhesion molecules • proto-oncogenes
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionNF-{kappa}B Plays a Central...References |
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Hypertension is a major risk factor for renal and cardiac damage; however, the mechanisms are incompletely understood. Angiotensin (Ang) II, the key effector of the local and circulating renin-angiotensin system (RAS), plays a central role.1 2 In addition to its vasoactive and growth-promoting action, Ang II stimulates circulating leukocytes and endothelial cells, thereby promoting inflammation and interstitial extracellular matrix accumulation.3 4 5 6 7 Many inflammation-mediating genes are activated by the transcription factor NF-
B (nuclear factor-B), which resides inactive and bound to the inhibitory protein I-B in the cytoplasm of T lymphocytes, monocytes, macrophages, endothelial cells, and smooth muscle cells.8 9 Ang II stimulates NADPH oxidase, which generates reactive oxygen species (ROS).10 ROS may act as signal transduction messengers for several important transcription factors, including NF-B and AP-1 (activator protein-1).11 Recently, Ozes et al12 showed that Akt/protein kinase B (Akt) is essential in tumor necrosis factor-
(TNF-)–induced activation of NF-B. Takahashi et al,13 as well as Ushio-Fukai et al,14 have demonstrated Akt activation by Ang II, which may involve ROS. Activation of Akt NF-B activates numerous genes, including interleukin (IL)-1, IL-6, IL-8, interferon-
, TNF-, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and the chemokine MCP-1 (monocyte chemoattractant protein-1). Several reports15 16 17 indicated that angiotensin converting enzyme (ACE) inhibition decreased NF-B in renal disease.
In vitro and in vivo studies showed that pyrrolidine dithiocarbamate (PDTC) was a potent inhibitor of NF-B but that it had no effect on AP-1, CREB (cAMP response element–binding protein), specificity protein (Sp-1), or octamer-binding proteins.18 19 The precise mechanism for the biological effects of PDTC is still controversial. Several studies have reported that metal-chelating, thiol-modifying, and oxygen radical–scavenging antioxidative properties mediate the inhibition of NF-B.19 However, in some biological systems, PDTC has been shown to exert pro-oxidative effects.20 21 This could mean that the inhibitory effect of redox-active substances is related to reductive as well as oxidative processes, most likely depending on the step in the signaling cascade with which they interfere. Other transcription factors, such as AP-1, are influenced by the redox status of the cell. AP-1 DNA binding is regulated by the redox modification of the c-jun and c-fos DNA binding domain.22 Cell culture studies have shown that PDTC induces AP-1 activity. These data suggest that AP-1 may function as an antioxidant responsive element.23 We recently observed that rats harboring both human renin and angiotensinogen genes (double-transgenic rats [dTGR]) develop severe renal and cardiac damage, accompanied by increased NF-B DNA binding activity, MCP-1 production, adhesion molecule expression, and inflammation, and that these rats die by 7 weeks of age.24 25 We investigated the hypothesis that PDTC inhibition of NF-B prevents inflammation and ameliorates cardiac and renal damage.
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Materials and Methods |
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Study Design
Experiments were conducted in 4-week-old male dTGR and age-matched Sprague-Dawley (SD) rats. The dTGR line and characteristics are described elsewhere.25 26 The rats were purchased from RCC (Füllinsdorf, Switzerland), kept in rooms at 24±2°C, fed a standard rat diet containing 0.2% sodium by weight, and allowed free access to tap water. All procedures were done according to guidelines from the American Physiological Society and were approved by local authorities (permit No. G 408/97). Fifteen dTGR received PDTC (Sigma) for 3 weeks once a day (200 mg/kg SC),27 28 whereas 15 dTGR and 15 SD rats received vehicle (0.9% NaCl). Systolic blood pressure was measured weekly by tail-cuff plethysmography under light ether anesthesia 20 hours after the last drug dose was administered. Urine samples were collected over a 24-hour period. Urinary rat albumin was measured with a commercially available ELISA (Celltrend). Rats were killed at 7 weeks of age. The kidneys and hearts were washed with ice-cold saline, blotted dry, and weighed. For electrophoretic mobility shift assay (EMSA) of NF-
B and AP-1 and for mRNA expression studies, the tissues were snap-frozen in liquid nitrogen (for immunohistochemistry, in isopentane [-35°C]), and stored at -80°C.
Immunohistochemistry
Frozen kidneys and hearts were cryosectioned at 6 µm thickness and air dried as described previously.25 29 The sections were fixed with cold acetone, washed with TBS, and incubated for 60 minutes in a humid chamber at room temperature with primary monoclonal antibodies against rat monocytes/macrophages (ED-1, Serotec), NF-B subunit p65 (Roche Boehringer), ICAM-1 (1A29, R&D Systems), and polyclonal inducible NO synthase (iNOS/NOS2) (ABR). After they were washed with TBS, the sections were incubated with a bridging antibody (rabbit anti-mouse IgG; Dako) for 30 minutes at room temperature and washed again with TBS. The APAAP complex (Dako) was applied, and the sections were incubated for 30 minutes at room temperature. Immunoreactivity was visualized by development in a mixture of naphthol AS-BI phosphate (Sigma) with Neufuchsin (Merck). Endogenous alkaline phosphatase was blocked by addition of 10 mmol/L levamisole (Sigma) to the substrate solution. The sections were slightly counterstained in Mayer’s hemalum (Merck), blued in tap water, and mounted with GelTol (Coulter-Immunotech). Immunostaining was performed as described previously.30 Semiquantitative scoring of ED-1–positive cells was performed by a computerized cell-counting program (KS 300 3.0, Zeiss). Fifteen different areas of each heart and kidney samples (n=5 in all groups) were analyzed. The samples were examined without knowledge of the identity of the rats.
Electrophoretic Mobility Shift Assay
Tissue extracts and EMSA for the transcription factor NF-B were performed as described previously.31 32 Briefly, frozen whole kidneys were pulverized in liquid nitrogen with mortar and pestle and resuspended in 3 mL of 50 mmol/L Tris (pH 7.4) containing a complete inhibitor tablet (Roche Boehringer) and 1 mmol/L Na-ortho-vanadate (Sigma Chemie). The suspension was centrifuged (4000g, 4 minutes, 4°C). The pellet was resuspended and lysed for 30 minutes in whole-cell lysate buffer (20 mmol/L HEPES, pH 7.9, 350 mmol/L NaCl, 20% glycerol, 1 mmol/L MgCl2, 0.5 mmol/L EDTA, 0.1 mmol/L EGTA, and 1% NP-40) and again centrifuged (13 000g, 10 minutes, 4°C). The supernatant was divided into aliquots and frozen in liquid nitrogen at -80°C until use. The protein concentration for EMSA and Western blot was quantified by the Bradford method. For EMSA, total renal homogenates (50 µg) were incubated in binding reaction medium (2 µg of poly dI-dC, 1 µg of BSA, 1 mmol/L DTT, 20 mmol/L HEPES, pH 8.4, 60 mmol/L KCl, and 8% Ficoll) with 0.5 ng of 32P-dATP end-labeled oligonucleotide containing the NF-B binding site from the major histocompatibility complex (MHC) enhancer (H2K, 5'-gatcCAGGGCTGGGGATTC-CCCATCTCCACAGG) at 30°C for 30 minutes. In competition assays, 50 or 100 ng of unlabeled H2K oligonucleotides were used. For supershift assay, 1 µg of anti-p50, anti-p65, anti-Rel B, and anti-c-Rel was added for 20 minutes to the homogenates before addition of the labeled probe. For AP-1, double-stranded oligonucleotides containing the consensus sequence for AP-1 (Santa Cruz, 5'-GAT CGA ACT GAC CGC CCG CCG CCC GT-3') were radiolabeled with g-32P with the use of T4 polynucleotide kinase by standard methods and purified over a column. The DNA-protein complexes were analyzed on a 5% polyacrylamide gel 0.5% Tris buffer, dried, and autoradiographed. In competition assays, 50 ng of unlabeled H2K or AP-1 oligonucleotides were used.
Isolation of mRNA and Gene Expression
RNA was isolated according to the Trizol protocol (Gibco-Life Technology). Reverse transcription–polymerase chain reaction (RT-PCR) primers and TaqMan probe for GAPDH, c-fos, and c-jun were constructed with the help of Primer Express (ABI Prism 7700, Perkin-Elmer) as follows: GAPDH forward, AAGCTGGTCATCAATGGGAAAC; GAPDH reverse, ACCCCATTTGATGTTAGCGG; GAPDH probe CATCACCATCTTCCAGGAGCGCGCGAT, FAM (6-carboxytetrafluorescein), and TAMRA (quencher) labeled; c-jun forward, TGAAAGCGCAAAACTCCGA; c-jun reverse, TGTGCCACCTGTTCCCTGA; c-jun probe FAM-CTGGCGTCCACGGCCAACATG-TAMRA; c-fos forward, CCATGATGTTCTCGGGTTTCA; c-fos reverse, GCGCTACTGCAGCGGG; c-fos probe FAM-CGCGGACTACGAGGCGTCA-TCC-TAMRA. Oligonucleotides were synthesized by BioTez. Manganese and primer concentrations were optimized with a titration curve. GAPDH Mn 3 mmol/L; c-jun 4 mmol/L; c-fos 4 mmol/L; GAPDH and c-jun: primer forward 300 nmol/L, primer reverse 300 nmol/L, probe 100 nmol/L; c-fos primer 200 nmol/L, probe 100 nmol/L. Real-time quantitative RT-PCR was performed with the TaqMan system (ABI Prism 7700, Perkin-Elmer) and according to the instructions of the TaqMan EZ RT-PCR TaqMan-kit protocol. RNA (0.5 to 1 µg total) was used for each PCR with the following time course: 50°C, 2 minutes; 60°C, 30 minutes; 95°C, 5 minutes; and 40 cycles of 94°C, 20 seconds, and 60°C, 1 minute. Each sample was tested in doublets. For quantification, gene expression of the target sequence was normalized in relation to the expressed housekeeping gene GAPDH.
Statistical Analysis
Data are presented as mean±SEM. Statistically significant differences in mean values were tested by ANOVA and the Tukey multiple range test. A value of P<0.05 was considered statistically significant. The data were analyzed with SYSTAT statistical software.
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Results |
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dTGR featured hypertension, severe renal damage, and cardiac hypertrophy with focal necrosis. Six (40%) of 15 untreated dTGR died before the end of the study at 7 weeks. None of the PDTC-treated dTGR and nontransgenic SD rats died before the end of the study (P<0.05). Small vessels showed increased intimal and medial thickness, as well as hyaline deposits. The renal tubules were frequently swollen and filled with proteinaceous material. Chronic treatment with PDTC prevented vascular injury in small renal vessels and extracellular matrix formation.
dTGR showed a progressive increase in systolic blood pressure from 5 to 7 weeks. PDTC ameliorated the increase in systolic blood pressure in dTGR (162±8 versus 190±7 mm Hg). However, PDTC-treated dTGR showed elevated blood pressure compared with nontransgenic SD rats (162±8 versus 107±2 mm Hg; P<0.001; n=8 to 15; Figure 1A). PDTC partially prevented the development of cardiac hypertrophy (Figure 1B). We found only a weak correlation between the reduction of blood pressure and attenuation of cardiac hypertrophy after PDTC treatment (r=0.46). Albuminuria (measured over 24 hours) progressively increased in untreated dTGR from 5 to 7 weeks. PDTC diminished but did not eliminate albuminuria in dTGR (2.5±0.8 versus 57.1±8.7 versus 0.3±0.1 mg/d at week 7; P<0.001; n=8 to 12; Figure 1C). Relative kidney weight was significantly higher in dTGR than in PDTC-treated rats and SD rats (4.9±0.1 versus 4.0±0.1 versus 3.7±0.1 mg/g body weight at week 7; P<0.001; n=8 to 15).
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First, we analyzed the effects of PDTC on monocytes/macrophages. There was significant infiltration in renal and cardiac tissue of dTGR. Monocytes/macrophages were localized primarily in the perivascular space in the heart and around the renal tubules but not in the glomeruli (data not shown). Treatment with PDTC prevented cell infiltration almost completely in both tissues. Semiquantitative cell-count analysis confirmed the significant reduction of monocyte/macrophage infiltration in the kidney and heart after PDTC treatment (P<0.001; Figure 1D). ICAM-1 expression in the kidney was increased in the intima, adventitia, and the perivascular space of the small vessels in untreated dTGR. Glomeruli and tubules also showed increased ICAM-1 expression. Expression of ICAM-1 was markedly reduced by treatment with PDTC and was similar to the constitutive ICAM-1 expression in control animals at week 7 (Figure 2, A through C). These results demonstrate that PDTC treatment reduced mononuclear cell infiltration and inhibited the expression of adhesion molecules.
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Next, we investigated the effects of PDTC on iNOS expression. We observed a strong increase in iNOS expression in the glomeruli in the vessel walls of renal arterioles (Figure 2, D through F). Treatment with PDTC greatly reduced iNOS immunoreactivity both in the blood vessels and in the glomeruli. Furthermore, we investigated the activation of the transcription factors NF-B and AP-1, which are main regulators of ICAM-1 and iNOS gene expression. Immunohistochemistry (phase contrast resolution) shows the localization of the NF-B subunit p65 in a cardiac vessel. Expression of p65 was increased in the endothelium and smooth muscle cells (Figure 3A), as well as in the vessel wall, infiltrated cells, glomeruli, and tubules (data not shown) of dTGR kidneys. PDTC markedly reduced p65 expression (Figure 3B). No immunoreaction was observed in nontransgenic SD rats (Figure 3C). The antibody recognizes an epitope overlapping the nuclear location signal of the p65 subunit and therefore selectively stains released, activated NF-B after dissociation from its inhibitor, I-B.33 We used EMSA for the detection of NF-B DNA binding activity in the kidney (Figure 4A) and heart (Figure 4D). NF-B DNA binding activity in the kidney was markedly reduced by PDTC treatment and even more so in the heart. Each lane in Figure 4 represents a separate animal. Renal homogenates were incubated with antibodies against the NF-B subunits anti-p50, anti-p65, anti-c-Rel, and anti-Rel B (Figure 4B). Binding specificity was demonstrated by competition of excess unlabeled oligonucleotides containing the kB site from the MHC enhancer (H2K) (Figure C). AP-1 activity was increased in dTGR kidneys compared with SD (Figure 5A). However, PDTC treatment did not reduce AP-1 binding activity. Binding specificity was demonstrated by competition of excess unlabeled oligonucleotides containing the AP-1 site (Figure 5B). Semiquantitative RT-PCR (TaqMan analysis) showed significantly increased c-jun and c-fos mRNA expression in the left ventricle of dTGR hearts (Figure 5, C through D). Chronic treatment with PDTC reduced c-fos but not c-jun mRNA (Figure 5, C through D).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionNF-{kappa}B Plays a Central...References |
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We tested the hypothesis that inhibition of NF-
B prevents inflammatory responses and ameliorates cardiac and renal damage. NF-B plays a critical role in the transcriptional activation of multiple genes that contribute to the development of end-organ damage. We found that NF-B inhibition prevented inflammatory responses, ameliorated cardiac and renal damage, and prevented death in all cases. Chronic PDTC treatment decreased blood pressure and cardiac hypertrophy slightly but almost completely eliminated albuminuria. The modest decrease in blood pressure was probably related to amelioration of renal failure rather than the result of a vasodilator effect. We do not believe that the blood pressure–lowering effect of PDTC had a major influence on end-organ protection, because effective Ang II–independent, antihypertensive triple treatment (hydralazine, reserpine, and hydrochlorothiazide) merely delayed organ damage and did not reduce inflammation.30 We used rats overexpressing the human renin and angiotensinogen genes because of the utility and severity of this model. We previously reported that renin can be taken up into tissues, leading to local Ang II formation.34 In contrast, Ang II infusions act in the circulation. Therefore, the dTGR model is suitable to study the effect of locally and systemically generated Ang II on cardiac and renal damage. We have also used 2-kidney 1-clip hypertension to induce end-organ damage.3 However, the reproducibility of that model is not as reliable as that reported here. Nevertheless, similar changes in terms of ICAM-1 expression, inflammation, and matrix production are also featured in that model. Thus, we believe that our results are relevant to other models of high Ang II.
We showed previously that Ang II production in the kidneys and elsewhere is responsible for this severe vasculopathy.24 Ang II stimulates various signaling pathways that lead to NF-B activation. Ang II stimulates NADPH oxidase, which generates ROS.10 ROS may act as signal transduction messengers for several important transcription factors, including NF-B and AP-1.11 35 36 Recently, 2 groups demonstrated that Ang II also stimulates Akt serine-threonine kinase.13 14 Furthermore, Ozes et al12 showed that Akt is essential in TNF-–induced activation of NF-B. PDTC is a potent inhibitor of NF-B.37 Schreck et al19 and Liu et al18 demonstrated that PDTC inhibited NF-B activation of various stimulants but had no effect on AP-1, CREB, Sp-1, and octamer-binding proteins in several cell lines and in vivo. In our study, PDTC markedly decreased NF-B binding activity in the heart and kidney, whereas AP-1 in the kidney and c-jun mRNA expression in the heart were not decreased. Only left ventricular c-fos expression was reduced by PDTC. Abate et al22 showed that AP-1 DNA binding is regulated by the redox modification of conserved cysteine residues in the DNA binding domain of c-jun and c-fos. Meyer et al23 suggested that AP-1 may function as an antioxidant responsive element. Thus, unchanged AP-1 activity in PDTC-treated dTGR may have also accounted for the antioxidative effect of PDTC. On the other hand, Ang II is known to stimulate immediate early genes, cell proliferation, and hypertrophic response.38 39 40 41 Recently, 2 groups39 41 showed that Ang II induced c-fos, c-jun, and AP-1 activity in vascular smooth muscle cells. Nakamura et al38 found that administration of antioxidants inhibited cardiac hypertrophy. In our model, chronic treatment with PDTC partially reduced cardiac hypertrophy. However, semiquantitative RT-PCR analysis showed that only c-fos mRNA and not c-jun was reduced in the left ventricle. However, to discern the differential contributions of c-jun, c-fos, and AP-1 on end-organ damage, more detailed analyses of signaling pathways using specific inhibitors of AP-1 will be required.
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NF-B Plays a Central Role in Various Cardiovascular Diseases
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionNF-{kappa}B Plays a Central...References |
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Ruiz-Ortega et al17 reported that NF-
B activation and MCP-1 expression in the renal cortex was reduced by ACE inhibition in experimental immune complex nephritis. Morrissey and Klahr16 showed that ACE inhibition decreased NF-B in kidneys with ureteral obstruction. Recently, Rangan et al28 demonstrated that NF-B inhibition by PDTC reduced inflammation and tubulointerstitial injury in nonimmune proteinuric rats. Myocardial and renal reperfusion injury develops to a large extent subsequent to the complex interaction of multiple cytokines and activated adhesion molecules.8 29 42 Morishita et al42 demonstrated that NF-B inhibition by a decoy technique reduced the extent of myocardial infarction after reperfusion. Hernandez-Presa et al15 have shown that ACE inhibition prevents arterial NF-B activation, chemokine expression, and macrophage infiltration in early accelerated atherosclerosis. We performed immunohistochemical analysis for the NF-B subunit p65, because in contrast to the p50 subunit, p65 contains the transcription activation domain. The antibody recognizes an epitope overlapping the nuclear location signal of the p65 subunit and therefore selectively stains released, activated NF-B after dissociation from its inhibitor, I-B.33 The NF-B subunit p65 was increased in the endothelium, in smooth muscle cells of damaged small vessels, and in infiltrated cells in dTGR. The staining pattern resembled the localization of p65 expression in atherosclerotic lesions.
Untreated dTGR show a 150-fold increased albuminuria. Remuzzi and coworkers7 43 44 45 demonstrated that increased glomerular permeability is followed by increased filtration of macromolecules, followed by excessive tubular protein reabsorption. This process leads to abnormal accumulation of proteins in endolysosomes and endoplasmic reticulum. Altogether, these processes foster the activation of NF-B–dependent and –independent cytokines, resulting in renal inflammation. Chronic inhibition of NF-B by PDTC probably inhibited both the direct activation of NF-B by Ang II and the subsequent activation induced by the increased glomerular permeability in our model, thereby breaking the self-amplifying loop.
We also examined inducible NO synthase (iNOS). Promoter deletion and mutation studies in cultured cells demonstrated that NF-B plays a critical role in transcriptional regulation of the iNOS gene induced by various cytokines.46 47 48 49 NO regulates numerous physiological and pathophysiological processes, including smooth muscle contractility, platelet reactivity, and the cytotoxic activity of leukocytes. However, inappropriate release of this mediator has been linked to the pathogenesis of a number of disease states.50 Although endothelial NO serves beneficial roles as a messenger and host defense molecule, excessive NO production by inducible NOS can be cytotoxic. Indeed, peroxynitrite anion formation, protein tyrosine nitration, and hydroxyl radical production may contribute to the evolution of several commonly encountered renal diseases, including postischemic renal failure, obstructive nephropathy, and renal allograft rejection, among others.51 Our data show that inhibition of NF-B by PDTC markedly reduces inflammation, iNOS expression in dTGR (most likely leading to decreased cytotoxicity), and cell proliferation. Thus, NF-B activation plays an important role in Ang II–induced end-organ damage.
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Acknowledgments |
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This study was supported by a grant-in-aid from Hoffmann-La Roche, Basel, Switzerland. Eero Mervaala was supported by the Alexander von Humboldt Foundation, the klinisch-pharmakologischer Verbund Berlin-Brandenburg, the Finnish Foundation for Cardiovascular Research, and the Academy of Finland. Christel Lipka, Mathilde Schmidt, and Karin Dressler gave expert technical assistance.
Received September 14, 1999; first decision October 26, 1999; accepted November 10, 1999.
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C. Dechow, C. Morath, J. Peters, I. Lehrke, R. Waldherr, V. Haxsen, E. Ritz, and J. Wagner Effects of all-trans retinoic acid on renin-angiotensin system in rats with experimental nephritis Am J Physiol Renal Physiol, November 1, 2001; 281(5): F909 - F919. [Abstract] [Full Text] [PDF]
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H. D. Intengan and E. L. Schiffrin Vascular Remodeling in Hypertension: Roles of Apoptosis, Inflammation, and Fibrosis Hypertension, September 1, 2001; 38(3): 581 - 587. [Abstract] [Full Text] [PDF]
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M. Katoh, Y. Kurosawa, K. Tanaka, A. Watanabe, H. Doi, and H. Narita Fluvastatin inhibits O2- and ICAM-1 levels in a rat model with aortic remodeling induced by pressure overload Am J Physiol Heart Circ Physiol, August 1, 2001; 281(2): H655 - H660. [Abstract] [Full Text] [PDF]
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R. Dechend, A. Fiebeler, J.-K. Park, D. N. Muller, J. Theuer, E. Mervaala, M. Bieringer, D. Gulba, R. Dietz, F. C. Luft, et al. Amelioration of Angiotensin II-Induced Cardiac Injury by a 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor Circulation, July 31, 2001; 104(5): 576 - 581. [Abstract] [Full Text] [PDF]
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M. Ruiz-Ortega, O. Lorenzo, M. Ruperez, J. Blanco, and J. Egido Systemic Infusion of Angiotensin II into Normal Rats Activates Nuclear Factor-{{kappa}}B and AP-1 in the Kidney : Role of AT1 and AT2 Receptors Am. J. Pathol., May 1, 2001; 158(5): 1743 - 1756. [Abstract] [Full Text] [PDF]
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E. M. A. Mervaala, Z. J. Cheng, I. Tikkanen, R. Lapatto, K. Nurminen, H. Vapaatalo, D. N. Muller, A. Fiebeler, U. Ganten, D. Ganten, et al. Endothelial Dysfunction and Xanthine Oxidoreductase Activity in Rats With Human Renin and Angiotensinogen Genes Hypertension, February 1, 2001; 37(2): 414 - 418. [Abstract] [Full Text] [PDF]
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Z. J. Cheng, T. Vaskonen, I. Tikkanen, K. Nurminen, H. Ruskoaho, H. Vapaatalo, D. Muller, J.-K. Park, F. C. Luft, and E. M. A. Mervaala Endothelial Dysfunction and Salt-Sensitive Hypertension in Spontaneously Diabetic Goto-Kakizaki Rats Hypertension, February 1, 2001; 37(2): 433 - 439. [Abstract] [Full Text] [PDF]
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F. C. Luft Workshop: Mechanisms and Cardiovascular Damage in Hypertension Hypertension, February 1, 2001; 37(2): 594 - 598. [Abstract] [Full Text] [PDF]
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R. A. Beswick, H. Zhang, D. Marable, J. D. Catravas, W. D. Hill, and R. C. Webb Long-Term Antioxidant Administration Attenuates Mineralocorticoid Hypertension and Renal Inflammatory Response Hypertension, February 1, 2001; 37(2): 781 - 786. [Abstract] [Full Text] [PDF]
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A. Fiebeler, F. Schmidt, D. N. Muller, J.-K. Park, R. Dechend, M. Bieringer, E. Shagdarsuren, V. Breu, H. Haller, and F. C. Luft Mineralocorticoid Receptor Affects AP-1 and Nuclear Factor-{{kappa}}B Activation in Angiotensin II-Induced Cardiac Injury Hypertension, February 1, 2001; 37(2): 787 - 793. [Abstract] [Full Text] [PDF]
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J. Sadoshima Cytokine Actions of Angiotensin II Circ. Res., June 23, 2000; 86(12): 1187 - 1189. [Full Text] [PDF]
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