Renal and Vascular Injury Induced by Exogenous Angiotensin II Is AT1 Receptor-Dependent

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Abstract

Angiotensin II (Ang II) infusion in rats augments vascular injury in balloon-injured carotid arteries and induces marked vascular and tubulointerstitial injury in kidneys. We examined how the AT1 receptor is modulated and whether blockade of the receptor with losartan could prevent the phenotypic and cellular changes. We also examined the role of the local renin-angiotensin system (RAS) by examining the expression of angiotensin-converting enzyme (ACE) and the effect of treatment with the ACE inhibitor, ramipril. Ang II infusion resulted in systemic hypertension and accelerated intimal and medial thickening in balloon-injured carotid arteries. Renal injury was manifested by proteinuria, glomerular phenotypic changes (mesangial expression of α-actin and podocyte expression of desmin), and tubulointerstitial injury with the tubular upregulation of the macrophage-adhesive protein, osteopontin, the interstitial accumulation of macrophages and myofibroblasts, and the deposition of collagen types III and IV. Ang II infusion decreased AT1 receptor number in the renal interstitium but not in glomeruli. Losartan completely blocked the Ang II-mediated hypertension, proteinuria, and injury to both carotid and kidney. Ang II infusion was also associated with an increase in ACE protein in both the proximal tubular brush border as well as at interstitial sites of injury, but despite evidence for activation of the local RAS, treatment with ramipril was without effect. These studies demonstrate that the renal and vascular injury induced by Ang II infusion is mediated by the AT1 receptor despite downregulation of the receptor in the interstitium. In addition, although there is evidence for local RAS activation, the injury appears to be mediated solely by the exogenous Ang II.

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Upregulation of renin-angiotensin system during differentiation of monocytes to macrophages.

K Moriguchi, H Rakugi, M Ohishi … (1999)

We have demonstrated that accumulated macrophages in human coronary arteries strongly express angiotensin converting enzyme in accordance with the development of atheromatous plaques. However, there are few reports on the regulation of the renin-angiotensin system in macrophages and in monocytes as their source. To examine whether the renin-angiotensin system is upregulated during the differentiation of monocytes to macrophages, and whether it is further regulated by angiotensin II and cytokines. We used a human leukemia cell line, THP-1, for monocytes. Differentiated THP-1, induced by adding phorbol 12-myristate 13-acetate for 24 h, were used as macrophages. Expression of messenger RNA of the renin-angiotensin system components was measured by quantitative reverse-transcriptase polymerase chain reaction. Angiotensin converting enzyme activity and subtype-specific angiotensin-binding sites of cultured cells, and angiotensin II production in the culture medium were measured. Macrophages expressed all components of the renin-angiotensin system except chymase. Cellular angiotensin converting enzyme activity and angiotensin II in the medium were increased 3.2- and 4.5-fold during differentiation, respectively. Expression of angiotensin II type 1 (AT1) and type 2 (AT2) receptors was increased 6.2-and 6.4-fold during differentiation, and was sustained for 7 days. Incubation with angiotensin II for 24 h caused downregulation of both AT1 and AT2 receptor messenger RNA, but the expression levels were still more than threefold higher compared with monocytes. The density of binding sites of AT1 and AT2 receptors in macrophages was 0.26 +/- 0.02 and 0.15 +/- 0.01 fmol/10(6) cells, respectively. The renin-angiotensin system is markedly activated during monocyte/macrophage differentiation, and may participate in the development of atherosclerosis.

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Regulation of proximal tubular osteopontin in experimental hydronephrosis in the rat.

Nágila Ricardo, R Kreisberg-Zakarin, Don J. Diamond … (1998)

Osteopontin is a tubular-derived glycoprotein with macrophage chemoattractant properties. Our previous observations demonstrate that osteopontin is involved in the accumulation of macrophages within the renal cortex of rats following unilateral ureteral obstruction (UUO). The present study performed Northern and Western blot analyses of isolated proximal tubular cells exposed to exogenous angiotensin II, and cultured rat proximal tubular cells subjected to one hour of cyclic mechanical stretch, which provided insight into mechanisms involving the proximal tubular renin-angiotensin system in the increased expression of cortical osteopontin following hydronephrosis. In situ hybridization, using a 35S-labeled antisense riboprobe, showed osteopontin mRNA transcription localized to the cortical tubules of the obstructed kidney. Freshly isolated proximal tubules incubated with angiotensin II (10-5 M) for one hour had increased osteopontin mRNA and protein expression by Northern and Western blot analyses, respectively. Pre-treatment of proximal tubules with losartan (10-5 M) for one hour prior to the addition of exogenous angiotensin II (10-5 M) decreased osteopontin mRNA and protein expression. Rat proximal tubule cells subjected to cyclic mechanical stretch for one hour exhibited a 2.1-fold increment in osteopontin mRNA levels, which was normalized following pre-treatment with losartan. This study provides evidence that angiotensin II, produced by the proximal tubule in the obstructed kidney as a result of mechanical injury, possibly mechanical stretch, may stimulate angiotensin II type I receptor activation, leading to up-regulated osteopontin expression and secretion by the proximal tubule, thereby facilitating macrophage recruitment into the renal interstitium.

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Author and article information

Journal

Journal ID (publisher-id): NEF

Journal ID (nlm-ta): Nephron

Journal ID (doi): 10.1159/issn.1660-8151

Title: Nephron

Publisher: S. Karger AG

ISSN (Print): 1660-8151

ISSN (Electronic): 2235-3186

Publication date Subscription-year: 2001

Publication date (Print): 2001

Publication date (Electronic): 22 January 2001

Volume: 87

Issue: 1

Pages: 66-74

Affiliations

^aDepartment of Pathology, University of Washington, Vascular Biology, Seattle,Wash., ^bSection of Pharmacology, National Institute of Mental Health, Bethesda,Md., USA; ^cDepartmento de Ciencias Fisiologicas, Facultad de Ciencias Biologicas, Pontificia Universidad Catolica de Chile, Santiago, Chile; ^dDivision of Nephrology, University of Washington, School of Medicine, Seattle,Wash., USA

Article

Publisher ID: 45886 Other ID: Nephron 2001;87:66–74

DOI: 10.1159/000045886

PubMed ID: 11174028

SO-VID: e32dcda4-7e03-49e1-b0d3-e4ed4db24240

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Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

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Figures: 3, Tables: 1, References: 45, Pages: 9

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