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

Theuer J, Dechend R, Muller DN, Park JK, Fiebeler A, Barta P, Ganten D, Haller H, Dietz R, Luft FC - BMC Cardiovasc Disord (2002)

Bottom Line: 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 markedly reduced the immunoreactivity of p65.Our data show that inhibition of NF-kappaB by PDTC markedly reduces inflammation, iNOS expression in the dTGR most likely leading to decreased cytotoxicity, and cell proliferation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Franz Volhard Clinic, Charite' and Max Delbrück Center for Molecular Medicine, Berlin, Humboldt University of Berlin, Germany. theuer@fvk-berlin.de

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-kB 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-kappaB binding activity in heart and kidney. Immunohistochemical analysis shows increased expression of the p65 NF-kappaB 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-kappaB by PDTC markedly reduces inflammation, iNOS expression in the dTGR most likely leading to decreased cytotoxicity, and cell proliferation. Thus, NF-kappaB activation plays an important role in ANG II-induced end-organ damage.

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Related in: MedlinePlus

Representative immunohistochemical photomicrograph of ED-1 in the heart of SD animals.
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Figure 8: Representative immunohistochemical photomicrograph of ED-1 in the heart of SD animals.

Mentions: There was significant infiltration in cardiac and renal perivascular space of dTGR compared to SD. Fig. 7 and 8 show a representative immunohistochemistry for ED1, a marker for macophages in the heart and in the kidney (9 and 10). Fig. 24 shows semiquantative scoring for macrophage-monocyte-infiltration of ED-1 in the kidney and in the heart. This was perforned using a computerized cell count programm.


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

Theuer J, Dechend R, Muller DN, Park JK, Fiebeler A, Barta P, Ganten D, Haller H, Dietz R, Luft FC - BMC Cardiovasc Disord (2002)

Representative immunohistochemical photomicrograph of ED-1 in the heart of SD animals.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC65512&req=5

Figure 8: Representative immunohistochemical photomicrograph of ED-1 in the heart of SD animals.
Mentions: There was significant infiltration in cardiac and renal perivascular space of dTGR compared to SD. Fig. 7 and 8 show a representative immunohistochemistry for ED1, a marker for macophages in the heart and in the kidney (9 and 10). Fig. 24 shows semiquantative scoring for macrophage-monocyte-infiltration of ED-1 in the kidney and in the heart. This was perforned using a computerized cell count programm.

Bottom Line: 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 markedly reduced the immunoreactivity of p65.Our data show that inhibition of NF-kappaB by PDTC markedly reduces inflammation, iNOS expression in the dTGR most likely leading to decreased cytotoxicity, and cell proliferation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Franz Volhard Clinic, Charite' and Max Delbrück Center for Molecular Medicine, Berlin, Humboldt University of Berlin, Germany. theuer@fvk-berlin.de

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-kB 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-kappaB binding activity in heart and kidney. Immunohistochemical analysis shows increased expression of the p65 NF-kappaB 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-kappaB by PDTC markedly reduces inflammation, iNOS expression in the dTGR most likely leading to decreased cytotoxicity, and cell proliferation. Thus, NF-kappaB activation plays an important role in ANG II-induced end-organ damage.

Show MeSH
Related in: MedlinePlus