(Hypertension. 1999;33:389-395.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Monocyte Infiltration and Adhesion Molecules in a Rat Model of High Human Renin Hypertension
From Franz Volhard Clinic, Medical Faculty of the Charite', Humboldt University of Berlin (Germany) (E.M.A.M., D.N.M., J.-K.P., F.S., M.L., D.D., H.H., F.C.L.); the Institute of Biomedicine, University of Helsinki (Finland) (E.M.A.M.); Max Delbrück Center for Molecular Medicine, Berlin, Germany (J.-K.P., M.L., D.G., F.C.L.); Hoffmann-La Roche, Basel, Switzerland (V.B.); and Institute for Clinical Pharmacology, Benjamin Franklin University Hospital, Free University of Berlin (Germany) (D.G.).
Correspondence to Friedrich C. Luft, Franz Volhard Clinic, Wiltberg Strasse 50, 13125 Berlin, FRG. E-mail luft{at}fvk-berlin.de
Abstract—Hypertension and kidney
damage in the double transgenic rat (dTGR) harboring both human renin
and human angiotensinogen genes are dependent on the human
components of the renin angiotensin system. We tested the
hypothesis that monocyte infiltration and increased adhesion molecule
expression are involved in the pathogenesis of kidney damage in dTGR.
We also evaluated the effects of long-term
angiotensin-converting enzyme (ACE) inhibition,
AT1 blockade, and human renin inhibition on monocyte
recruitment and inflammatory response in dTGR. Systolic blood
pressure and 24-hour albuminuria were markedly increased in
7-week-old dTGR as compared with age-matched normotensive Sprague
Dawley rats. We found a significant monocyte/macrophage
infiltration in the renal perivascular space and increased expression
of intercellular adhesion molecule-1 (ICAM-1) and vascular cell
adhesion molecule-1 (VCAM-1) in the interstitium, intima, and
adventitia of the small renal vessels. 
Lß2
integrin and 4ß1 integrin, the
corresponding ligands for ICAM-1 and VCAM-1, were also found on
infiltrating monocytes/macrophages. The expression of
plasminogen activator inhibitor-1
and fibronectin in the kidneys of dTGR were increased and distributed
similarly to ICAM-1. In 4-week-old dTGR, long-term treatment with ACE
inhibition (cilazapril), AT1 receptor blockade (valsartan),
and human renin inhibition (RO 65-7219) (each drug 10 mg/kg by gavage
once a day for 3 weeks) completely prevented the development of
albuminuria. However, only cilazapril and valsartan were
able to decrease blood pressure to normotensive levels. Interestingly,
the drugs were all equally effective in preventing
monocyte/macrophage infiltration and the overexpression of
adhesion molecules, plasminogen activator
inhibitor-1, and fibronectin in the kidney. Our findings
indicate that angiotensin II causes monocyte recruitment
and vascular inflammatory response in the kidney by blood
pressure–dependent and blood pressure–independent mechanisms. ACE
inhibition, AT1 receptor blockade, and human renin
inhibition all prevent monocyte/macrophage infiltration and
increased adhesion molecule expression in the kidneys of dTGR.
Key Words: angiotensin II • intercellular adhesion molecule-1 • vascular cell adhesion molecule-1 • plasminogen activator inhibitor-1 • fibronectin • renin
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