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Angiotensin II induced inflammation in the kidney and in the heart of double transgenic rats

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Item Type:Article
Title:Angiotensin II induced inflammation in the kidney and in the heart of double transgenic rats
Creators Name:Theuer, J. and Dechend, R. and Muller, D.N. and Park, J.K. and Fiebeler, A. and Barta, P. and Ganten, D. and Haller, H. and Dietz, R. and Luft, F.C.
Abstract:BACKGROUND: We are investigating a double transgenic rat (dTGR) model, in which rats transgenic for the human angiotensinogen and renin genes are crossed. These rats develop moderately severe hypertension but die of end-organ cardiac and renal damage by week 7. The heart shows necrosis and fibrosis, whereas the kidneys resemble the hemolytic-uremic syndrome vasculopathy. Surface adhesion molecules (ICAM-1 and VCAM-1) are expressed early on the endothelium, while the corresponding ligands are found on circulating leukocytes. Leukocyte infiltration in the vascular wall accompanies PAI-1, MCP-1, iNOS and Tissue Factor expression. Furthermore we show evidence that Ang II causes the upregulation of NF-{kappa}B in our model. METHODS: We started PDTC-treatment on four weeks old dTGR (200 mg/kg sc) and age-matched SD rats. Blood-pressure- and albuminuria- measurements were monitored during the treatment period (four weeks). The seven weeks old animals were killed, hearts and kidneys were isolated and used for immunohistochemical-and electromobility shift assay analysis. RESULTS: Chronic treatment with the antioxidant PDTC decreased blood pressure (162 plus minus 8 vs. 190 plus minus 7 mm Hg, p = 0.02). Cardiac hypertrophy index was significantly reduced (4.90 plus minus 0.1 vs. 5.77 plus minus 0.1 mg/g, p < 0.001) compared to dTGR. PDTC reduced 24 h albuminuria by 85 % (2.7 plus minus 0.5 vs. 18.0 plus minus 3.4 mg/d, p < 0.001) and prevented death significantly. Vascular injury was ameliorated in small renal and cardiac vessels. PDTC inhibited NF-{kappa}B binding activity in heart and kidney. Immunohistochemical analysis shows increased expression of the p65 NF-{kappa}B subunit in the endothelium, smooth muscles cells of damaged small vessels, infiltrated cells, glomeruli, tubuli and collecting ducts of dTGR. PDTC markedly reduced the immunoreactivity of p65. CONCLUSION: Our data show that inhibition of NF-{kappa}B by PDTC markedly reduces inflammation, iNOS expression in the dTGR most likely leading to decreased cytotoxicity, and cell proliferation. Thus, NF-{kappa}B activation plays an important role in ANG II-induced end-organ damage.
Keywords:Angiotensin II, Angiotensinogen, Animal Models, Genetically Modified Animals, Cardiomegaly, Electrophoretic Mobility Shift Assay, Enzyme Inhibitors, Heart, Intercellular Adhesion Molecule-1, Kidney, Myocarditis, NF-{kappa} B, Necrosis, Nephritis, Nitric Oxide Synthase, Oxidative Stress, Proline, Sprague-Dawley Rats, Renin, Thiocarbamates, Vascular Cell Adhesion Molecule-1, Animals, Rats
Source:BMC Cardiovascular Disorders
Publisher:BioMed Central
Page Range:3
Date:18 January 2002
Official Publication:https://doi.org/10.1186/1471-2261-2-3
PubMed:View item in PubMed

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