(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
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Abstract |
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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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Introduction |
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Hypertension is a major risk factor for renal injury. However, the mechanisms underlying the development and progression of hypertension-induced kidney damage are incompletely understood. There is growing evidence that vascular inflammatory responses and interstitial accumulation of extracellular matrix proteins are involved in the pathogenesis.1 2 Moreover, both experimental and clinical studies revealed that angiotensin II (Ang II), the key effector of the local and circulating renin-angiotensin system (RAS), plays a central role in the pathogenesis of hypertension-induced end-organ damage (for reviews see References 3 and 43 4 ). The mechanisms of Ang II–induced hypertension and renal damage are generally attributed to direct vasoconstriction, enhancement of sympathetic adrenergic transmission, and increased secretion of aldosterone and endothelins.3 4 However, recent studies have suggested that Ang II could also induce end-organ damage and endothelial dysfunction by production of oxidative stress5 and by enhancing leukocyte adhesion on endothelial cells.6 In rats, physiological and pharmacological experiments aimed at exploring the role of the RAS in hypertension is hampered by the species specificity of the renin-angiotensinogen interaction. The hypertension of double transgenic rat (dTGR) harboring the human renin and human angiotensinogen genes is dependent on the human RAS components.7 These rats offer a unique opportunity to study the human RAS and pharmacologically induced changes of the human RAS in an experimental animal model. 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. We showed that Ang II caused moderate hypertension and a progressive increase in albuminuria, induced monocyte/macrophage infiltration, and led to extensive adhesion molecule expression in the kidney that was followed by an increased expression of plasminogen activator inhibitor-1 (PAI-1) and fibronectin. Cilazapril, valsartan, and the human renin inhibitor were equally effective in preventing vascular inflammatory response, although only cilazapril and valsartan were able to decrease blood pressure to normotensive levels. Our findings suggest that Ang II causes monocyte/macrophage infiltration and vascular inflammatory responses in the kidneys by blood pressure–dependent and blood pressure–independent mechanisms.
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Methods |
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Experiments were conducted in 73 4-week-old male dTGR (body weight 58±1 g) and in 15 normotensive Sprague-Dawley rats (SD) (53±2 g). The dTGR line and characteristics are described in detail elsewhere.7 8 Briefly, the human renin construct used to generate transgenic animals made up the entire genomic human renin gene (10 exons and 9 introns), with 3.0 kB of the 5' promoter region and 1.2 kB of 3' additional sequences. The human angiotensinogen construct made up the entire human angiotensinogen gene (5 exons and 4 introns), with 1.3 kB of 5' flanking and 2.4 kB of 3' flanking sequences. The rats were purchased from Biological Research Laboratories Ltd (Füllinsdorf, Switzerland) and were allowed free access to standard 0.3% sodium rat chow (SSNIFF Spezialitäten GmbH) and drinking water. The procedures and experimental protocols were approved by the local Council on Animal Care, whose standards correspond to those of the American Physiological Society. Four-week-old dTGR were divided into 4 groups: (1) control group (n=26), (2) human renin inhibitor group (RO 65-7219) (n=15), (3) cilazapril group (n=16), and (4) losartan group (n=16). The drugs were given for 3 weeks by gavage once per day (10 mg/kg). Control dTGR and SD rats received vehicle (1% sodium carboxymethylcellulose). Systolic blood pressure was measured weekly by tail-cuff method under light ether anesthesia 20 hours after the last drug dose, starting at the age of 5 weeks. Urine samples were collected over a 24-hour period by metabolic cages at 5, 6, and 7 weeks. Ten dTGR and 5 SD rats were killed under pentobarbital anesthesia (65 mg/kg IP) at the age 5 weeks, whereas all other rats were killed at age 7 weeks. Whole blood samples for flow cytometry were taken into EDTA (4.5 mmol/L) tubes. The kidneys were washed with ice-cold saline and weighed. For immunohistochemistry, the kidney was cut sagittally, snap-frozen in isopentane (-35°C), and stored at -80°C. Frozen kidneys were processed and semiquantitative scoring performed as described in detail previously.9 Monoclonal antibodies against rat monocytes/macrophages (ED1) (Serotec, Oxford, England), intercellular adhesion molecule-1 (ICAM-1) (1A29) (R&D Systems),
Lß2 integrin
(WT0.1), vascular cell adhesion molecule-1 (VCAM-1) (51-10C9)
(Pharmingen, San Diego, Calif),
4ß1 integrin (TA-4)
(Pharmingen), and polyclonal antibodies against PAI-1 (American
Diagnostica, Greenwich, Conn) and fibronectin
(Paesel+Lorei, Frankfurt, Germany) were used. Light microscopic
techniques that we used are described in detail
elsewhere.7 8 9 The kidney samples were examined without
knowledge of the rat's identity group. Fluorescence sorting
analysis from circulating blood cells was carried out according
to the instructions of the manufacturer (Becton Dickinson) with
fluorochrome-conjugated monoclonal antibodies against rat
Lß2 integrin (CD11a)
(Serotec, Oxford, England). Quantitative determination of the monocyte
chemoattractant protein-1 (MCP-1) concentration in the urine and plasma
was performed with a commercially available rat MCP-1 ELISA kit
(Pharmingen). Urinary MCP-1 concentrations were normalized to
urine creatinine. Data are presented as mean±SEM. Statistically significant differences in mean values were tested by 2-way ANOVA for repeated measures and the Tukey's multiple range test. A value of P<0.05 was considered statistically significant. The data were analyzed with SYSTAT statistical software.
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Results |
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Cilazapril and valsartan treatment but not treatment with human renin inhibitor decreased blood pressure to levels observed in normotensive SD rats (Figure 1A
).
Systolic blood pressure of the human renin
inhibitor group was significantly decreased only when
measured 4 hours after drug administration (151±8 vs 178±4
mm Hg, P<0.05). There was a progressive increase in
24-hour albuminuria in untreated dTGR from 5 to 7 weeks
(Figure 1B). Human renin inhibitor, cilazapril, and
valsartan completely prevented the development of
albuminuria in dTGR (Figure 1B). Kidney weight was
significantly higher in dTGR (4.72±0.19 mg/g body wt) than in SD rats
(3.40±0.08 mg/g body wt) (P<0.001). All drug treatments
normalized kidney weight in dTGR (P<0.05 vs dTGR control
group). There was significant monocyte/macrophage infiltration
in the renal perivascular space in untreated dTGR (Figure 2). Increased ICAM-1 expression was
observed in the interstitium, intima, and adventitia of the small
vessels and in the glomerular capsule (Figure 2).
ICAM-1 increased over time (Table). The expression of
Lß2 integrin, the
corresponding ligand for ICAM-1, was also increased in infiltrated
monocytes/macrophages as well as in leukocytes (Figure 3). The VCAM-1 and its counterreceptor
4ß1 integrin
expressions were increased mostly at 5 weeks and remained only
moderately increased at 7 weeks (Figure 4). The expression of PAI-1 and
fibronectin were distributed similarly to ICAM-1 and also increased
over time (Figure 5). The vessels of
7-week-old untreated dTGR showed increased intimal and medial
thickening and hyaline deposits. The tubules were frequently swollen
and filled with proteinaceous material, whereas the glomeruli were
usually not affected (data not shown). Long-term treatment with human
renin inhibitor (Figures 2 through 5), cilazapril,
and valsartan all prevented monocyte/macrophage infiltration
and adhesion molecule expression in the kidneys (Table). The
drug treatments also blocked the morphological changes observed in
untreated dTGR (data not shown).
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MCP-1 concentration in urine was increased 
130% in dTGR compared
with normotensive SD rats (Figure 6A).
Human renin inhibitor, cilazapril, and valsartan decreased
urinary MCP-1 concentration to levels found in SD rats. There was no
difference between the treatment groups in plasma MCP-1 concentrations
(Figure 6B).
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Discussion |
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The dTGR harboring both human renin and human angiotensinogen genes feature relatively moderate hypertension with severe vascular lesions in the kidneys and the heart.7 We showed recently that pressure-natriuresis-diuresis curves in dTGR are shifted toward higher renal perfusion pressure ranges by Ang II–dependent mechanisms inherent to the kidneys themselves.8 The main findings here were that dTGR developed severe albuminuria that was associated with pronounced monocyte/macrophage infiltration and renal expression of surface adhesion molecules ICAM-1 and VCAM-1. We also demonstrated increased expression of
Lß2 integrin and
4ß1 integrin, the
counterreceptors for ICAM-1 and VCAM-1, on penetrating
monocytes/macrophages as well as circulating inflammatory
cells. Whereas ICAM-1 expression was constantly increased over time,
the increased expression of VCAM-1 was most prominent in the early
phase of renal injury. The monocyte recruitment in the vascular wall
was accompanied by increased PAI-1 expression in the same areas and
accumulation of extracellular matrix protein. Human renin
inhibitor, ACE inhibitor, and
AT1 receptor antagonist treatment
prevented the development of albuminuria, monocyte
recruitment, and vascular inflammatory response. Our findings indicate
that the development of kidney injury in dTGR is dependent on Ang II
and is associated with pronounced vascular inflammatory response and
overexpression of adhesion molecules ICAM-1 and VCAM-1. We sought to elucidate mechanisms involved in the pathogenesis of renal injury in dTGR. Long-term Ang II infusion in normotensive rats results in moderate hypertension and marked vascular, glomerular, and tubulointerstitial injury and interstitial fibrosis.10 In dTGR, arterial hypertension induced by the human components of the RAS causes mechanical stress to endothelial and smooth muscle cells that may in part account for the development of renal vascular damage. Even though hemodynamic forces alone are capable of inducing vascular remodeling and subsequent end-organ damage, blood pressure–independent mechanisms mediated by high Ang II levels are also likely to be involved. Our finding that human renin inhibitor completely prevented the development of albuminuria as well as monocyte/macrophage infiltration and overexpression of adhesion molecules in the kidneys with only a partial decrease in blood pressure supports this notion. We would like to underline the fact that our monoclonal antibody used for the detection of infiltrating cells detects mainly rat monocytes and macrophages. However, it is likely that other inflammatory cells, such as neutrophils and myofibroblasts, are also involved in the inflammatory response in dTGR. Furthermore, even though we were able to demonstrate a close association between monocyte recruitment, overexpression of adhesion molecules, and the development of albuminuria, the present study does not give direct evidence that inflammatory cell infiltrate mediates renal injury in dTGR.
The underlying mechanisms of the Ang II–dependent vascular
inflammatory response and expression of adhesion molecules are only
poorly understood. McCarron et al11 12 have shown
previously that cytokine or endotoxin-stimulated ICAM-1
expression and monocyte adhesion is more intense on
endothelial cells derived from SHR compared with cells
from WKY rats, indicating that hypertension may enhance responsiveness
of endothelium to factors that promote monocyte
adhesion. However, inconsistent with this report,
Komatsu et al13 demonstrated recently that
constitutive ICAM-1 expression in the microvasculature does not differ
between WKY and SHR in vivo. Ang II induces leukocyte adhesion on human
endothelial cells at least in vitro and modulates the
expression of E-selectin, an adhesion molecule that has been implicated
in initiating cellular contact between leukocytes and
endothelium and that plays a central role in the
leukocyte "rolling" phenomenon under blood-flow
conditions.6 The present study describes that Ang II
induces surface molecules ICAM-1 and VCAM-1 in the vascular
endothelium as well as their counterreceptors
Lß2 integrin and
4ß1 integrin in the
circulating and infiltrating monocytes. Consistent with our
findings, Mai et al2 have demonstrated previously that
ICAM-1 expression increases progressively in kidneys exposed to high
blood pressure in the high renin phase of 2-kidney 1-clip Goldblatt
model. Here we also showed that vascular inflammatory response as well
as the overexpression of the adhesion molecules in the kidneys can be
prevented effectively by drugs interfering the RAS.
We observed copious PAI-1 expression in the kidneys of dTGR. PAI-1 is a major physiological inhibitor of the plasminogen activator/plasmin system, a key regulator of fibrinolysis and extracellular matrix turnover.14 Activation of the RAS can disturb the balance of the fibrinolytic system by stimulating excess production of PAI-1 and thereby increasing the risk of thrombotic events. We have not studied this pathway in greater detail; however, untreated dTGR given high salt (unpublished observations) show accentuated renal damage with microthrombi and fibrin deposition. These same mechanisms are probably active on a smaller scale here. RAS blockade ameliorates these mechanisms.
Our double transgenic rat model of high human renin hypertension allowed us to examine species-specific human renin inhibitor in rats. At the dose tested, the human renin inhibitor RO 65-7219 decreased blood pressure significantly less than cilazapril and valsartan. In fact, the modest blood pressure lowering effect by RO 65-7219 was observed only after 4 hours. Previous pharmacokinetic studies have shown that human renin inhibitors have very high hepatic clearance and low oral efficacy.15 An unfavorable pharmacokinetic profile is likely to explain the lack of any significant antihypertensive effect by RO 65-7219 in dTGR. However, the uptake of human renin inhibitors by the kidney may act as reservoir for the drug, resulting in the prolonged duration of pharmacological activity locally. We conclude that moderate hypertension and severe albuminuria is highly dependent on Ang II in the dTGR model. Ang II is able to induce pronounced monocyte recruitment and vascular inflammatory responses in the kidney by blood pressure–dependent and blood pressure–independent mechanisms. ACE inhibition, AT1 receptor blockade, and human renin inhibition prevent monocyte/macrophage infiltration and increased adhesion molecule expression in dTGR.
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Acknowledgments |
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This study was supported by a grant-in-aid from Hofmann-La Roche, Basel, Switzerland. Eero Mervaala was supported by the Alexander von Humboldt Foundation, the Finnish Cultural Foundation, the Finnish Foundation for Cardiovascular Research, and the Academy of Finland. Christel Lipka and Marion Somnitz gave expert technical assistance. Eero Mervaala and Dominik Müller contributed equally to this work.
Received September 17, 1998; first decision October 14, 1998; accepted October 23, 1998.
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 R. Rocha, C. L. Martin-Berger, P. Yang, R. Scherrer, J. Delyani, and E. McMahon Selective Aldosterone Blockade Prevents Angiotensin II/Salt-Induced Vascular Inflammation in the Rat Heart Endocrinology, December 1, 2002; 143(12): 4828 - 4836. [Abstract] [Full Text] [PDF]
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Y. Sun, J. Zhang, L. Lu, S. S. Chen, M. T. Quinn, and K. T. Weber Aldosterone-Induced Inflammation in the Rat Heart : Role of Oxidative Stress Am. J. Pathol., November 1, 2002; 161(5): 1773 - 1781. [Abstract] [Full Text] [PDF]
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R. Rocha, A. E. Rudolph, G. E. Frierdich, D. A. Nachowiak, B. K. Kekec, E. A. G. Blomme, E. G. McMahon, and J. A. Delyani Aldosterone induces a vascular inflammatory phenotype in the rat heart Am J Physiol Heart Circ Physiol, November 1, 2002; 283(5): H1802 - H1810. [Abstract] [Full Text] [PDF]
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 D. Harding, P. B. Baines, D. Brull, V. Vassiliou, I. Ellis, A. Hart, A. P. J. Thomson, S. E. Humphries, and H. E. Montgomery Severity of Meningococcal Disease in Children and the Angiotensin-Converting Enzyme Insertion/Deletion Polymorphism Am. J. Respir. Crit. Care Med., April 15, 2002; 165(8): 1103 - 1106. [Abstract] [Full Text] [PDF]
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 I. L. Noronha, C. K. Fujihara, and R. Zatz The inflammatory component in progressive renal disease--are interventions possible? Nephrol. Dial. Transplant., March 1, 2002; 17(3): 363 - 368. [Full Text] [PDF]
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K. F. Hilgers, A. Hartner, M. Porst, R. Veelken, and J. F.E. Mann Angiotensin II Type 1 Receptor Blockade Prevents Lethal Malignant Hypertension: Relation to Kidney Inflammation Circulation, September 18, 2001; 104(12): 1436 - 1440. [Abstract] [Full Text] [PDF]
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C. U. Chae, R. T. Lee, N. Rifai, and P. M. Ridker Blood Pressure and Inflammation in Apparently Healthy Men Hypertension, September 1, 2001; 38(3): 399 - 403. [Abstract] [Full Text] [PDF]
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 A. Alvarez and M.-J. Sanz Reactive oxygen species mediate angiotensin II-induced leukocyte-endothelial cell interactions in vivo J. Leukoc. Biol., August 1, 2001; 70(2): 199 - 206. [Abstract] [Full Text] [PDF]
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E. M. A. Mervaala, Z. J. Cheng, I. Tikkanen, R. Lapatto, K. Nurminen, H. Vapaatalo, D. N. Muller, A. Fiebeler, U. Ganten, D. Ganten, et al. Endothelial Dysfunction and Xanthine Oxidoreductase Activity in Rats With Human Renin and Angiotensinogen Genes Hypertension, February 1, 2001; 37(2): 414 - 418. [Abstract] [Full Text] [PDF]
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Z. J. Cheng, T. Vaskonen, I. Tikkanen, K. Nurminen, H. Ruskoaho, H. Vapaatalo, D. Muller, J.-K. Park, F. C. Luft, and E. M. A. Mervaala Endothelial Dysfunction and Salt-Sensitive Hypertension in Spontaneously Diabetic Goto-Kakizaki Rats Hypertension, February 1, 2001; 37(2): 433 - 439. [Abstract] [Full Text] [PDF]
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F. C. Luft Workshop: Mechanisms and Cardiovascular Damage in Hypertension Hypertension, February 1, 2001; 37(2): 594 - 598. [Abstract] [Full Text] [PDF]
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A. Kiarash, P. J. Pagano, M. Tayeh, N.-E. Rhaleb, and O. A. Carretero Upregulated Expression of Rat Heart Intercellular Adhesion Molecule-1 in Angiotensin II- but Not Phenylephrine- Induced Hypertension Hypertension, January 1, 2001; 37(1): 58 - 65. [Abstract] [Full Text] [PDF]
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C. K. Fujihara, D. M. Avancini Costa Malheiros, I. de Lourdes Noronha, G. De Nucci, and R. Zatz Mycophenolate Mofetil Reduces Renal Injury in the Chronic Nitric Oxide Synthase Inhibition Model Hypertension, January 1, 2001; 37(1): 170 - 175. [Abstract] [Full Text] [PDF]
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G. Caimi, R. L. Presti, C. Carollo, M. Musso, F. Porretto, B. Canino, A. Catania, and G. Cerasola Polymorphonuclear Integrins, Membrane Fluidity, and Cytosolic Ca2+ Content After Activation in Essential Hypertension Hypertension, November 1, 2000; 36(5): 813 - 817. [Abstract] [Full Text] [PDF]
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L. Piqueras, P. Kubes, A. Alvarez, E. O'Connor, A. C. Issekutz, J. V. Esplugues, and M.-J. Sanz Angiotensin II Induces Leukocyte-Endothelial Cell Interactions In Vivo Via AT1 and AT2 Receptor-Mediated P-Selectin Upregulation Circulation, October 24, 2000; 102(17): 2118 - 2123. [Abstract] [Full Text] [PDF]
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D. N. Muller, E. M. A. Mervaala, F. Schmidt, J.-K. Park, R. Dechend, E. Genersch, V. Breu, B.-M. Loffler, D. Ganten, W. Schneider, et al. Effect of Bosentan on NF-{kappa}B, Inflammation, and Tissue Factor in Angiotensin II-Induced End-Organ Damage Hypertension, August 1, 2000; 36(2): 282 - 290. [Abstract] [Full Text] [PDF]
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D. N. Muller, E. M. A. Mervaala, R. Dechend, A. Fiebeler, J.-K. Park, F. Schmidt, J. Theuer, V. Breu, N. Mackman, T. Luther, et al. Angiotensin II (AT1) Receptor Blockade Reduces Vascular Tissue Factor in Angiotensin II-Induced Cardiac Vasculopathy Am. J. Pathol., July 1, 2000; 157(1): 111 - 122. [Abstract] [Full Text] [PDF]
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 M. d. Gasparo, P. Hess, B. Nuesslein-Hildesheim, P. Bruneval, and J.-P. Clozel Combination of non-hypotensive doses of valsartan and enalapril improves survival of spontaneously hypertensive rats with endothelial dysfunction Journal of Renin-Angiotensin-Aldosterone System, June 1, 2000; 1(2): 151 - 158. [Abstract] [PDF]
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M. de Gasparo New basic science initiatives with the angiotensin II receptor blocker valsartan Journal of Renin-Angiotensin-Aldosterone System, June 1, 2000; 1(2_suppl): S3 - S5. [Abstract] [PDF]
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 T. Tsutamoto, A. Wada, K. Maeda, N. Mabuchi, M. Hayashi, T. Tsutsui, M. Ohnishi, M. Sawaki, M. Fujii, T. Matsumoto, et al. Angiotensin II type 1 receptor antagonist decreases plasma levels of tumor necrosis factor alpha, interleukin-6 and soluble adhesion molecules in patients with chronic heart failure J. Am. Coll. Cardiol., March 1, 2000; 35(3): 714 - 721. [Abstract] [Full Text] [PDF]
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M. E. Pueyo, W. Gonzalez, A. Nicoletti, F. Savoie, J.-F. Arnal, and J.-B. Michel Angiotensin II Stimulates Endothelial Vascular Cell Adhesion Molecule-1 via Nuclear Factor-{kappa}B Activation Induced by Intracellular Oxidative Stress Arterioscler Thromb Vasc Biol, March 1, 2000; 20(3): 645 - 651. [Abstract] [Full Text] [PDF]
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 C. K. FUJIHARA, I. DE LOURDES NORONHA, D. M. A. C. MALHEIROS, G. R. ANTUNES, I. B. DE OLIVEIRA, and R. ZATZ Combined Mycophenolate Mofetil and Losartan Therapy Arrests Established Injury in the Remnant Kidney J. Am. Soc. Nephrol., February 1, 2000; 11(2): 283 - 290. [Abstract] [Full Text] [PDF]
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E. Mervaala, D. N. Muller, F. Schmidt, J.-K. Park, V. Gross, M. Bader, V. Breu, D. Ganten, H. Haller, and F. C. Luft Blood Pressure-Independent Effects in Rats With Human Renin and Angiotensinogen Genes Hypertension, February 1, 2000; 35(2): 587 - 594. [Abstract] [Full Text] [PDF]
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D. N. Muller, R. Dechend, E. M. A. Mervaala, J.-K. Park, F. Schmidt, A. Fiebeler, J. Theuer, V. Breu, D. Ganten, H. Haller, et al. NF-{kappa}B Inhibition Ameliorates Angiotensin II-Induced Inflammatory Damage in Rats Hypertension, January 1, 2000; 35(1): 193 - 201. [Abstract] [Full Text] [PDF]
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E. Mervaala, D. N. Muller, J.-K. Park, R. Dechend, F. Schmidt, A. Fiebeler, M. Bieringer, V. Breu, D. Ganten, H. Haller, et al. Cyclosporin A Protects Against Angiotensin II-Induced End-Organ Damage in Double Transgenic Rats Harboring Human Renin and Angiotensinogen Genes Hypertension, January 1, 2000; 35(1): 360 - 366. [Abstract] [Full Text] [PDF]
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E. MERVAALA, B. DEHMEL, V. GROSS, A. LIPPOLDT, J. BOHLENDER, A. F. MILIA, D. GANTEN, and F. C. LUFT Angiotensin-Converting Enzyme Inhibition and AT1 Receptor Blockade Modify the Pressure-Natriuresis Relationship by Additive Mechanisms in Rats with Human Renin and Angiotensinogen Genes J. Am. Soc. Nephrol., August 1, 1999; 10(8): 1669 - 1680. [Abstract] [Full Text]
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