Abstract
BackgroundWe 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-kB in our model.MethodsWe 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 treatement period (four weeks). The seven weeks old animals were killed, hearts and kidneys were isolated and used for immunohistochemical-and electromobility shift assay analsis.ResultsChronic treatment with the antioxidant PDTC decreased blood pressure (162 ± 8 vs. 190 ± 7 mm Hg, p = 0.02). Cardiac hypertrophy index was significantly reduced (4.90 ± 0.1 vs. 5.77 ± 0.1 mg/g, p < 0.001) compared to dTGR. PDTC reduced 24 h albuminuria by 85 % (2.7 ± 0.5 vs. 18.0 ± 3.4 mg/d, p < 0.001) and prevented death significantly. Vascular injury was ameliorated in small renal and cardiac vessels. PDTC inhibited NF-κB binding activity in heart and kidney. Immunohistochemical analysis shows increased expression of the p65 NF-κB 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.ConclusionOur data show that inhibition of NF-κB by PDTC markedly reduces inflammation, iNOS expression in the dTGR most likely leading to decreased cytotoxicity, and cell proliferation. Thus, NF-κB activation plays an important role in ANG II-induced end-organ damage.
Highlights
Hypertension injures blood vessels and thereby causes end-organ damage
Cardiac hypertrophy is one of the leading features in double transgenic rat (dTGR)
PAI-1 and fibronectin expression were increased in the perivascular space and adventitia of dTGR compared to Sprague Dawley (SD) (Fig. 3,4,5,6)
Summary
Hypertension injures blood vessels and thereby causes end-organ damage. The mechanisms are complicated and, studied for decades in experimental animal models, are only currently being elucidated [1] The endothelial layer acts as a signal transduction interface for hemo-dynamic forces in the regulation of vascular tone and chronic structural remodeling of arteries. Effects of mechanical forces on signal transduction and gene expression in endothelial cells have been demonstrated [2]. Oxyradical production by endothelial cells can result in leukocyte-endothelial adhesion responses that involve transcription-independent and -dependent surface expression of different endothelial cell adhesion molecules. Infiltration of the permeabilized endothelium by leukocytes sets the stage for an inflammatory cascade, involving cytokines, chemokines, growth factors, and matrix metalloproteinases. 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. We show evidence that Ang II causes the upregulation of NF-kB in our model
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