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

BMC Cardiovasc Disord. 2002;2:3. doi: 10.1186/1471-2261-2-3. Epub 2002 Jan 18.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / adverse effects*
  • Angiotensinogen / genetics
  • Animals
  • Animals, Genetically Modified
  • Cardiomegaly / chemically induced
  • Cardiomegaly / prevention & control
  • Electrophoretic Mobility Shift Assay
  • Enzyme Inhibitors / pharmacology
  • Heart / drug effects*
  • Humans
  • Intercellular Adhesion Molecule-1 / metabolism
  • Kidney / drug effects*
  • Kidney / metabolism
  • Kidney / pathology
  • Models, Animal
  • Myocarditis / chemically induced
  • Myocarditis / prevention & control*
  • NF-kappa B / metabolism*
  • Necrosis
  • Nephritis / chemically induced
  • Nephritis / prevention & control*
  • Nitric Oxide Synthase / metabolism
  • Nitric Oxide Synthase Type II
  • Oxidative Stress
  • Proline / analogs & derivatives*
  • Proline / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Renin / genetics
  • Renin / metabolism
  • Thiocarbamates / pharmacology
  • Vascular Cell Adhesion Molecule-1 / metabolism


  • Enzyme Inhibitors
  • NF-kappa B
  • Thiocarbamates
  • Vascular Cell Adhesion Molecule-1
  • Angiotensinogen
  • Angiotensin II
  • Intercellular Adhesion Molecule-1
  • prolinedithiocarbamate
  • Proline
  • NOS2 protein, human
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, rat
  • Renin