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      Suppressive Effects of Iron on TGF-β 1 Production by Renal Proximal Tubular Epithelial Cells


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          Background: TGF-β<sub>1</sub>, which is one of the profibrogenic cytokines, is considered essential for both the tubulointerstitial fibrosis found in chronic kidney diseases and the repair of tissue damage in acute renal injury. Iron plays an important part in inflammatory damage since it supplies cytotoxic hydroxyl radicals. The aim of the present study was to examine the direct effects of iron on TGF-β<sub>1</sub> production and the expression of 8-hydroxy-2′-deoxyguanosine (8-OHdG), a marker of oxidative stress, by human renal proximal tubular epithelial cells (RPTEC). Methods: Using human RPTEC, TGF-β<sub>1</sub> expression was studied by immunohistochemical staining, ELISA and RNase protection assays. 8-OHdG expression was evaluated by immunohistochemical staining. Results: Ferric iron suppressed both TGF-β<sub>1</sub> secretion and mRNA expression, and enhanced 8-OHdG expression in RPTEC in a dose-dependent manner. Desferrioxamine, an iron chelator, eliminated the suppressive effect of ferric citrate on TGF-β<sub>1</sub> production. Conclusions: The results suggest that iron may delay the repair of kidney injury during the acute inflammatory phase via a reduction in TGF-β<sub>1</sub> production by RPTEC. Iron chelation may therefore be a useful strategy in the treatment of inflammatory kidney diseases.

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          Most cited references24

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          Transforming growth factor beta in tissue fibrosis.

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            Pathophysiology of progressive nephropathies.

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              Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-beta antibody in db/db diabetic mice.

              Emerging evidence suggests that transforming growth factor-beta (TGF-beta) is an important mediator of diabetic nephropathy. We showed previously that short-term treatment with a neutralizing monoclonal anti-TGF-beta antibody (alphaT) in streptozotocin-diabetic mice prevents early changes of renal hypertrophy and increased matrix mRNA. To establish that overactivity of the renal TGF-beta system mediates the functional and structural changes of the more advanced stages of nephropathy, we tested whether chronic administration of alphaT prevents renal insufficiency and glomerulosclerosis in the db/db mouse, a model of type 2 diabetes that develops overt nephropathy. Diabetic db/db mice and nondiabetic db/m littermates were treated intraperitoneally with alphaT or control IgG, 300 microgram three times per week for 8 wk. Treatment with alphaT, but not with IgG, significantly decreased the plasma TGF-beta1 concentration without decreasing the plasma glucose concentration. The IgG-treated db/db mice developed albuminuria, renal insufficiency, and glomerular mesangial matrix expansion associated with increased renal mRNAs encoding alpha1(IV) collagen and fibronectin. On the other hand, treatment with alphaT completely prevented the increase in plasma creatinine concentration, the decrease in urinary creatinine clearance, and the expansion of mesangial matrix in db/db mice. The increase in renal matrix mRNAs was substantially attenuated, but the excretion of urinary albumin factored for creatinine clearance was not significantly affected by alphaT treatment. We conclude that chronic inhibition of the biologic actions of TGF-beta with a neutralizing monoclonal antibody in db/db mice prevents the glomerulosclerosis and renal insufficiency resulting from type 2 diabetes.

                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                May 2005
                03 March 2005
                : 100
                : 1
                : e1-e10
                aDepartment of Endocrinology, Metabolism and Nephrology, and bDepartment of Tumor Pathology, Kochi Medical School, Nankoku, Japan
                84107 Nephron Exp Nephrol 2005;100:e1–e10
                © 2005 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.

                : 31 March 2004
                : 17 August 2004
                Page count
                Figures: 8, References: 40, Pages: 1
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/84107
                Self URI (text/html): https://www.karger.com/Article/FullText/84107
                Self URI (journal page): https://www.karger.com/SubjectArea/Nephrology
                Original Paper

                Cardiovascular Medicine,Nephrology
                8-OHdG,Hematuria,Oxidative stress,Tubulointerstitial fibrosis,Proteinuria,Cytokine


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