NF-κB Inhibition Ameliorates Angiotensin II–Induced Inflammatory Damage in Rats

We recently reported that the activation of nuclear factor-kappaB (NF-kappaB) 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-kappaB 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-kappaB 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 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-kappaB 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-kappaB 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-kappaB-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-kappaB activity, ameliorates inflammation, and protects against angiotensin II-induced end-organ damage.

[1]  森口 泰孝 Angiotensin 2-induced transactivation of epidermal growth factor receptor regulates fibronectin and transforming growth factor-β synthesis via transcriptional and posttranscriptional mechanisms , 2000 .

[2]  A. Malik,et al.  Inhibition of NF-kappaB activation by pyrrolidine dithiocarbamate prevents In vivo expression of proinflammatory genes. , 1999, Circulation.

[3]  L. Pfeffer,et al.  NF-κB activation by tumour necrosis factor requires the Akt serine–threonine kinase , 1999, Nature.

[4]  R. Alexander,et al.  Reactive Oxygen Species Mediate the Activation of Akt/Protein Kinase B by Angiotensin II in Vascular Smooth Muscle Cells* , 1999, The Journal of Biological Chemistry.

[5]  Shokei Kim,et al.  Contribution of extracellular signal-regulated kinase to angiotensin II-induced transforming growth factor-beta1 expression in vascular smooth muscle cells. , 1999, Hypertension.

[6]  Y. Wang,et al.  Inhibition of nuclear factor-κB activation reduces cortical tubulointerstitial injury in proteinuric rats , 1999 .

[7]  U. Kikkawa,et al.  Activation of Akt/protein kinase B after stimulation with angiotensin II in vascular smooth muscle cells. , 1999, American journal of physiology. Heart and circulatory physiology.

[8]  Y. Mori,et al.  Angiotensin II-induced transactivation of epidermal growth factor receptor regulates fibronectin and transforming growth factor-beta synthesis via transcriptional and posttranscriptional mechanisms. , 1999, Circulation research.

[9]  N. Perico,et al.  Antiproteinuric therapy while preventing the abnormal protein traffic in proximal tubule abrogates protein- and complement-dependent interstitial inflammation in experimental renal disease. , 1999, Journal of the American Society of Nephrology : JASN.

[10]  P. Delafontaine,et al.  Distinct and Common Pathways in the Regulation of Insulin-like Growth Factor-1 Receptor Gene Expression by Angiotensin II and Basic Fibroblast Growth Factor* , 1999, The Journal of Biological Chemistry.

[11]  S. Moncada,et al.  Inhibition of nitric oxide synthase as a potential therapeutic target. , 1999, Annual review of pharmacology and toxicology.

[12]  D. Ganten,et al.  Hypertension-induced end-organ damage : A new transgenic approach to an old problem. , 1999, Hypertension.

[13]  D. Ganten,et al.  Monocyte infiltration and adhesion molecules in a rat model of high human renin hypertension. , 1999, Hypertension.

[14]  J. Egido,et al.  ACE inhibitor quinapril reduces the arterial expression of NF-kappaB-dependent proinflammatory factors but not of collagen I in a rabbit model of atherosclerosis. , 1998, The American journal of pathology.

[15]  R. Busse,et al.  Glucocorticoids inhibit superoxide anion production and p22 phox mRNA expression in human aortic smooth muscle cells. , 1998, Hypertension.

[16]  G. Remuzzi,et al.  Pathophysiology of progressive nephropathies. , 1998, The New England journal of medicine.

[17]  S. Klahr The role of L‐arginine in hypertension and nephrotoxicity , 1998, Current opinion in nephrology and hypertension.

[18]  K. Mihara,et al.  Inhibitory effects of antioxidants on neonatal rat cardiac myocyte hypertrophy induced by tumor necrosis factor-alpha and angiotensin II. , 1998, Circulation.

[19]  F. Luft,et al.  ICAM-1 antisense oligodesoxynucleotides prevent reperfusion injury and enhance immediate graft function in renal transplantation. , 1998, Kidney international.

[20]  B. Altura,et al.  Pyrrolidine dithiocarbamate attenuates alcohol-induced leukocyte-endothelial cell interaction and cerebral vascular damage in rats: possible role of activation of transcription factor NF-kappaB in alcohol brain pathology. , 1998, Alcohol.

[21]  J. Egido,et al.  Angiotensin II participates in mononuclear cell recruitment in experimental immune complex nephritis through nuclear factor-kappa B activation and monocyte chemoattractant protein-1 synthesis. , 1998, Journal of immunology.

[22]  G. Remuzzi,et al.  In progressive nephropathies, overload of tubular cells with filtered proteins translates glomerular permeability dysfunction into cellular signals of interstitial inflammation. , 1998, Journal of the American Society of Nephrology : JASN.

[23]  J. Ménard,et al.  Local angiotensin II generation in the rat heart: role of renin uptake. , 1998, Circulation research.

[24]  P. Ridker,et al.  Plasma concentration of soluble intercellular adhesion molecule 1 and risks of future myocardial infarction in apparently healthy men , 1998, The Lancet.

[25]  W. Hsueh,et al.  Integrins, adhesion, and cardiac remodeling. , 1998, Hypertension.

[26]  A. Malik,et al.  In vivo inhibition of nuclear factor-kappa B activation prevents inducible nitric oxide synthase expression and systemic hypotension in a rat model of septic shock. , 1997, Journal of immunology.

[27]  S. Klahr,et al.  Enalapril decreases nuclear factor κB activation in the kidney with ureteral obstruction: Rapid Communication , 1997 .

[28]  T. Ogihara,et al.  In vivo transfection of cis element “decoy” against nuclear factor- κB binding site prevents myocardial infarction , 1997, Nature Medicine.

[29]  G. Hillis,et al.  Importance of the tubulointerstitium in human glomerulonephritis. II. Distribution of integrin chains β1, α1 to 6 and αV , 1997 .

[30]  F. Luft,et al.  Leukocyte infiltration and ICAM-1 expression in two-kidney one-clip hypertension. , 1997, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[31]  M. Karin,et al.  Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. , 1997, The New England journal of medicine.

[32]  S. Klahr,et al.  Rapid communication. Enalapril decreases nuclear factor kappa B activation in the kidney with ureteral obstruction. , 1997, Kidney international.

[33]  G. Hillis,et al.  Importance of the tubulointerstitium in human glomerulonephritis. II. Distribution of integrin chains beta 1, alpha 1 to 6 and alpha V. , 1997, Kidney international.

[34]  J. Ménard,et al.  High human renin hypertension in transgenic rats. , 1997, Hypertension.

[35]  C. Scheidereit,et al.  Different mechanisms control signal‐induced degradation and basal turnover of the NF‐kappaB inhibitor IkappaB alpha in vivo. , 1996, The EMBO journal.

[36]  J. Redondo,et al.  Transcriptional up-regulation of intracellular adhesion molecule-1 in human endothelial cells by the antioxidant pyrrolidine dithiocarbamate involves the activation of activating protein-1. , 1996, Journal of immunology.

[37]  C. Lowenstein,et al.  Transcriptional regulation of iNOS by IL-1 beta in cultured rat pulmonary artery smooth muscle cells. , 1996, The American journal of physiology.

[38]  C. Patterson,et al.  Suppression of Interleukin-1β-induced Nitric-oxide Synthase Promoter/Enhancer Activity by Transforming Growth Factor-β1 in Vascular Smooth Muscle Cells , 1996, The Journal of Biological Chemistry.

[39]  G. Remuzzi,et al.  Glomerular protein trafficking and progression of renal disease to terminal uremia. , 1996, Seminars in nephrology.

[40]  C. Sen,et al.  Antioxidant and redox regulation of gene transcription , 1996, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[41]  R. Knuechel,et al.  Activated transcription factor nuclear factor-kappa B is present in the atherosclerotic lesion. , 1996, The Journal of clinical investigation.

[42]  C. Patterson,et al.  Suppression of interleukin-1beta-induced nitric-oxide synthase promoter/enhancer activity by transforming growth factor-beta1 in vascular smooth muscle cells. Evidence for mechanisms other than NF-kappaB. , 1996, The Journal of biological chemistry.

[43]  Jonathan D. Cohen,et al.  The Cytokine Responsive Vascular Smooth Muscle Cell Enhancer of Inducible Nitric Oxide Synthase , 1995, The Journal of Biological Chemistry.

[44]  S. Orrenius,et al.  Dithiocarbamates Induce Apoptosis in Thymocytes by Raising the Intracellular Level of Redox-active Copper (*) , 1995, The Journal of Biological Chemistry.

[45]  G. Natoli,et al.  Reactive Oxygen Intermediates Mediate Angiotensin II-induced c-Jun•c-Fos Heterodimer DNA Binding Activity and Proliferative Hypertrophic Responses in Myogenic Cells (*) , 1995, The Journal of Biological Chemistry.

[46]  W. Dröge,et al.  Distinct effects of glutathione disulphide on the nuclear transcription factor kappa B and the activator protein-1. , 1994, European journal of biochemistry.

[47]  P. Baeuerle,et al.  H2O2 and antioxidants have opposite effects on activation of NF‐kappa B and AP‐1 in intact cells: AP‐1 as secondary antioxidant‐responsive factor. , 1993, The EMBO journal.

[48]  U. Zabel,et al.  Nuclear uptake control of NF‐kappa B by MAD‐3, an I kappa B protein present in the nucleus. , 1993, The EMBO journal.

[49]  D. Männel,et al.  Dithiocarbamates as potent inhibitors of nuclear factor kappa B activation in intact cells , 1992, The Journal of experimental medicine.

[50]  J. Ingelfinger,et al.  Molecular biology of renal injury: emphasis on the role of the renin-angiotensin system. , 1991, Journal of the American Society of Nephrology : JASN.

[51]  K Lindpaintner,et al.  The cardiac renin-angiotensin system. An appraisal of present experimental and clinical evidence. , 1991, Circulation research.

[52]  T. Curran,et al.  Redox regulation of fos and jun DNA-binding activity in vitro. , 1990, Science.

[53]  D. Baltimore,et al.  NF-κB: A pleiotropic mediator of inducible and tissue-specific gene control , 1989, Cell.

[54]  D. Baltimore,et al.  NF-kappa B: a pleiotropic mediator of inducible and tissue-specific gene control. , 1989, Cell.