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      Increased Osteopontin Expression following Renal Ablation Is Attenuated by Angiotensin Type 1 Receptor Antagonism

      , ,

      Cardiorenal Medicine

      S. Karger AG

      Angiotensin II, Osteopontin, Renal failure

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          Abstract

          Osteopontin is an extracellular matrix protein that is upregulated in renal injury. The aim of this study was to explore the renal expression of osteopontin in a model of progressive renal injury following subtotal nephrectomy (STNx) in rats and the effects of angiotensin type1 (AT1) receptor antagonist irbesartan on osteopontin expression. STNx or a sham operation was performed in 8-week-old Sprague-Dawley rats. STNx rats were given either irbesartan (15 mg/g) or no treatment for 12 weeks. Upregulation of osteopontin mRNA expression was observed in injured renal tubules as assessed by in situ hybridization (42 ± 8 dpm/mm<sup>2</sup> v.s. control 7.7 ± 0.6 dpm/mm<sup>2</sup>, p < 0.01). Increased osteopontin expression was closely related to infiltration of monocytes/macrophages and increased cellular proliferation. Double immunohistochemical staining demonstrated co-existence of proliferating cell nuclear antigen and osteopontin positive staining in individual cells in kidney sections from STNx rats. The increase in osteopontin expression was inhibited by the AT1 receptor antagonist irbesartan (6.9 ± 1.2 dpm/mm<sup>2</sup>), associated with attenuation of impaired renal function and pathology as well as decreased monocyte/macrophage infiltration and cellular proliferation. These findings suggest that osteopontin is upregulated in STNx rats and is reduced by AT1 receptor antagonism.

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          Most cited references 3

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          De novo glomerular osteopontin expression in rat crescentic glomerulonephritis.

          Osteopontin (OPN) is a secreted acidic glycoprotein that has potent monocyte chemoattractant and adhesive properties. Up-regulation of tubular OPN expression is thought to promote interstitial macrophage infiltration in experimental nephritis; however, the role of OPN in glomerular lesions, particularly crescent formation, is unknown. The present study used Northern blotting, in situ hybridization and immunohistochemistry to examine OPN expression in a rat model of accelerated anti-GBM glomerulonephritis. Osteopontin mRNA and protein is expressed by some parietal epithelial cells, thick ascending limbs of Henle and medullary tubules and collecting ducts in normal rat kidney. De novo OPN mRNA and protein expression was evident in glomerular visceral and parietal epithelial cells in anti-GBM glomerulonephritis. Glomerular OPN expression preceded and correlated with macrophage infiltration in the development of hypercellularity, focal and segmental lesions and, notably, crescent formation. There was marked up-regulation of OPN expression by tubular epithelial cells that also preceded and correlated with interstitial macrophage (r = 0.93, P < 0.001) and T-cell infiltration (r = 0.85, P < 0.001). Both glomerular and tubular OPN expression correlated significantly with proteinuria (P < 0.001) and a reduction in creatinine clearance (P < 0.01). In addition, double immunohistochemistry showed co-expression of osteopontin and one of its ligands, CD44, in intrinsic renal cells. CD44 and OPN expression by parietal epithelial cells was evident in crescent formation, while virtually all OPN-positive tubules expressed CD44. Infiltrating macrophages and T-cells were CD44-positive, but only a small proportion of T-cells and few macrophages showed OPN expression. Interestingly, strong OPN mRNA and protein expression was seen in macrophage multinucleated giant cells. In summary, this study suggests that OPN promotes macrophage and T-cell infiltration in the development of renal lesions in rat anti-GBM glomerulonephritis, including glomerular crescent and multinucleated giant cell formation.
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            Link between Angiotensin II and TGF-β in the Kidney

             Gunter Wolf (1998)
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              Regulation of proximal tubular osteopontin in experimental hydronephrosis in the rat.

              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
                EXN
                Nephron Exp Nephrol
                10.1159/issn.1660-2129
                Cardiorenal Medicine
                S. Karger AG
                1660-2129
                2002
                2002
                09 January 2002
                : 10
                : 1
                : 19-25
                Affiliations
                Department of Medicine, University of Melbourne, Austin & Repatriation Medical Center, Heidelberg West, Vic.,Australia
                Article
                49894 Exp Nephrol 2002;10:19–25
                10.1159/000049894
                © 2002 S. Karger AG, Basel

                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.

                Page count
                Figures: 6, References: 23, Pages: 7
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/49894
                Categories
                Original Paper

                Cardiovascular Medicine, Nephrology

                Angiotensin II, Osteopontin, Renal failure

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