NF-κB Inhibition Ameliorates Angiotensin II–Induced Inflammatory Damage in Rats
Dominik N. Müller,Ralf Dechend,Eero Mervaala,Joon-Keun Park,Folke Schmidt,Anette Fiebeler,Jürgen Theuer,Volker Breu,Detlev Ganten,Hermann Haller,Friedrich C. Luft +10 more
TLDR
It is demonstrated that the antioxidant pyrrolidine dithiocarbamate inhibits NF-kappaB activity, ameliorates inflammation, and protects against angiotensin II-induced end-organ damage.Abstract:
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.read more
Citations
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Vascular Remodeling in Hypertension Roles of Apoptosis, Inflammation, and Fibrosis
TL;DR: The resulting remodeling of small arteries may initially be adaptive, but eventually it becomes maladaptive and compromises organ function, contributing to cardiovascular complications of hypertension.
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Inflammation and angiotensin II.
TL;DR: Recent data support the hypothesis that RAS is key mediator of inflammation, and further understanding of the role of the RAS in this process may provide important opportunities for clinical research and treatment of inflammatory diseases.
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Reactive oxygen species in vascular biology: implications in hypertension
TL;DR: The present chapter discusses the role of oxidative stress in vascular damage in hypertension and suggests therapies targeted against reactive oxygen intermediates, by decreasing generation of ROS and/or by increasing availability of antioxidants, may be useful in minimizing vascular injury and hypertensive end organ damage.
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Aldosterone-Induced Inflammation in the Rat Heart: Role of Oxidative Stress
TL;DR: In this paper, aldosterone (ALDO) was shown to induce a proinflammatory/fibrogenic phenotype in both right and left ventricles in response to ALDO/salt treatment and that would be sustained with chronic treatment.
Journal ArticleDOI
NF-κB in Renal Inflammation
Ana Belen Sanz,Maria Dolores Sanchez-Niño,Adrian M. Ramos,Juan Antonio Moreno,Beatriz Santamaría,Marta Ruiz-Ortega,Jesús Egido,Alberto Ortiz +7 more
TL;DR: Under most test conditions, specific NF-kappaB inhibitors tend to reduce inflammation in experimental kidney injury but not always, and although many drugs in current use clinically influence NF- kappaB activation, there are no data regarding specificNF-kappB inhibition in human kidney disease.
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