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      Enhanced Effect of Combined Treatment with SMP-534 (Antifibrotic Agent) and Losartan in Diabetic Nephropathy

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          Abstract

          Background/Aims: Diabetic nephropathy is now the most common cause of end-stage renal disease. It is also clear that the current therapy, angiotensin II blockage, cannot prevent the progression of diabetic nephropathy. We had previously demonstrated that an antifibrotic agent, SMP-534, reduced extracellular matrix production induced by transforming growth factor-β in vitro, and that SMP-534 prevented renal fibrosis and urinary albumin in diabetic db/db mice via a nonantihypertensive mechanism. We expected that combined use of SMP-534 and losartan would produce a more highly renoprotective action. Methods: We examined the effects of combined treatment with SMP-534 and losartan on urinary albumin and glomerular fibrosis in db/ db mice. Diet containing these agents was provided from age 9 to 25 weeks. Blood and urine analyses were performed at 8, 17, and 25 weeks. At the end of the study, kidney tissues were histologically analyzed. Results: SMP-534 significantly suppressed an increase in urinary albumin excretion and ameliorated the progression of glomerular fibrosis in db/db mice, whereas losartan did not. Combined treatment with SMP-534 and losartan markedly prevented the increase of urinary albumin excretion compared with treatment with either SMP-534 or losartan alone. In contrast, renal histological analysis revealed that combined treatment did not significantly prevent an increase of mesangial expansion in the kidney compared with treatment with SMP-534 alone. Conclusion: A combination of the two agents, SMP-534 and losartan, might be a valuable therapeutic approach for the treatment of diabetic nephropathy.

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          Most cited references 28

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          Pathophysiology of progressive nephropathies.

           T Bertani,  G. Remuzzi (1998)
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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.
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              Suppression of experimental glomerulonephritis by antiserum against transforming growth factor beta 1.

              Glomerulonephritis is an inflammation of the kidney characterized by the accumulation of extracellular matrix within the damaged glomeruli, impaired filtration and proteinuria. In its progressive form, the disease destroys kidney function leading to uraemia and death, unless dialysis therapy or kidney transplantation is available. The pathogenesis of glomerulonephritis is incompletely understood, but the eliciting factor is thought often to be an immunological injury to mesangial and/or other resident cells in the glomeruli. We have used an animal model of acute mesangial proliferative glomerulonephritis to show that this disease is associated with increased production and activity of transforming growth factor beta 1 (TGF-beta 1), an inducer of extracellular matrix production. Here we report that administration of anti-TGF-beta 1 at the time of induction of the glomerular disease suppresses the increased production of extracellular matrix and dramatically attenuates histological manifestations of the disease. These results provide direct evidence for a causal role of TGF-beta 1 in the pathogenesis of the experimental disease and suggest a new approach to the therapy of glomerulonephritis.
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                Author and article information

                Journal
                AJN
                Am J Nephrol
                10.1159/issn.0250-8095
                American Journal of Nephrology
                S. Karger AG
                0250-8095
                1421-9670
                2006
                April 2006
                05 April 2006
                : 26
                : 1
                : 50-58
                Affiliations
                Dainippon Sumitomo Pharma Co., Ltd., Drug Research Division, aPharmacology Research Laboratories, bChemistry Research Laboratories, cTechnology Research and Development Center, Chemical Synthesis Laboratories, Osaka, Japan
                Article
                91786 Am J Nephrol 2006;26:50–58
                10.1159/000091786
                16508247
                © 2006 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: 5, Tables: 1, References: 46, Pages: 9
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/91786
                Categories
                Original Report: Laboratory Investigation

                Cardiovascular Medicine, Nephrology

                Urinary albumin, Diabetic nephropathy, Fibrosis, Losartan

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