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(Hypertension. 1999;33:212-218.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Hypertension-Induced End-Organ Damage
A New Transgenic Approach to an Old Problem
From the Franz Volhard Clinic and Max Delbrück Center for Molecular Medicine, Medical Faculty of the Charité, Humboldt University of Berlin, Germany; and Department of Clinical Pharmacology, Benjamin Franklin University Hospital, Free University of Berlin.
Correspondence to Friedrich C. Luft, Franz Volhard Clinic, Wiltberg Str 50, 13122 Berlin, Germany. E-mail luft{at}fvk-berlin.de
Abstract—Angiotensin
(Ang) II-induced organ damage has fascinated students of hypertension
since the work of Wilson and Byrom. 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, and VEGF expression. The expression of
TGF-ß and deposition of extracellular matrix proteins follows, which
is accompanied by fibrinoid vasculitis in small vessels of the heart
and kidneys. Angiotensin-converting enzyme
inhibitors and AT1 receptor blockers each lowered blood
pressure and shifted pressure natriuresis partially leftward by
different mechanisms. When combined, they normalized blood pressure,
pressure natriuresis, and protected from vasculopathy completely. Renin
inhibition lowered blood pressure partially, but protected from
vasculopathy completely. Endothelin receptor blockade had no influence
on blood pressure but protected from vasculopathy and improved
survival. We show evidence that Ang II stimulates oxidative stress
directly or indirectly via endothelin 1 and that NF
B is upregulated
in this model. We speculate that the transcription factors NFB and
AP-1 are involved with initiating chemokine and cytokine
expression, leading to the above cascade. The unique model and our
pharmacological probes will enable us to test these hypotheses.
Key Words: angiotensin II • rats, transgenic • renin • nuclear factor-B • monocyte chemoattractant protein-1 • muscle, smooth, vascular • endothelium
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