Amelioration of Established Diabetic Nephropathy by Combined Treatment with SMP-534 (Antifibrotic Agent) and Losartan in  db/db  Mice

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Abstract

Background/Aims: Diabetic nephropathy is the main cause of end-stage renal disease. Previously we have demonstrated that SMP-534 (an antifibrotic agent) prevents the development of diabetic nephropathy in db/db mouse and that combined treatment with SMP-534 and losartan (antihypertensive agents) markedly prevents the development of diabetic nephropathy compared with single treatment. SMP-534 or losartan was prophylactically administered to db/db mice before the onset of diabetic nephropathy. In the present study, we evaluated the efficacy of combined treatment when administration was started after the onset of diabetic nephropathy. Methods: db/db mice were raised untreated until 17 weeks of age, by which time increase of urinary albumin was noted, and then treated with SMP-534 and/or losartan for another 8 weeks. Biochemical and histological analyses were performed at 25 weeks of age. Results: Combined treatment with SMP-534 and losartan markedly prevented the increase ofurinary albumin and ameliorated the progression of mesangial matrix expansion, even when administration was started long after the increase of urinary albumin. Conclusion: The study results indicate that a combination of SMP-534 and losartan might be a valuable therapeutic approach for the treatment of diabetic nephropathy even when administration is started after the onset of diabetic nephropathy.

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Most cited references 24

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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.

F Ziyadeh, B. B. Hoffman, D Han … (2000)

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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Reversal of lesions of diabetic nephropathy after pancreas transplantation.

M E Mauer, Donna Sutherland, F C Goetz … (1998)

In patients with type I diabetes mellitus who do not have uremia and have not received a kidney transplant, pancreas transplantation does not ameliorate established lesions of diabetic nephropathy within five years after transplantation, but the effects of longer periods of normoglycemia are unknown. We studied kidney function and performed renal biopsies before pancreas transplantation and 5 and 10 years thereafter in eight patients with type I diabetes but without uremia who had mild to advanced lesions of diabetic nephropathy at the time of transplantation. The biopsy samples were analyzed morphometrically. All patients had persistently normal glycosylated hemoglobin values after transplantation. The median urinary albumin excretion rate was 103 mg per day before transplantation, 30 mg per day 5 years after transplantation, and 20 mg per day 10 years after transplantation (P=0.07 for the comparison of values at base line and at 5 years; P=0.11 for the comparison between base line and 10 years). The mean (+/-SD) creatinine clearance rate declined from 108+/-20 ml per minute per 1.73 m2 of body-surface area at base line to 74+/-16 ml per minute per 1.73 m2 at 5 years (P<0.001) and 74+/-14 ml per minute per 1.73 m2 at 10 years (P<0.001). The thickness of the glomerular and tubular basement membranes was similar at 5 years (570+/-64 and 928+/-173 nm, respectively) and at base line (594+/-81 and 911+/-133 nm, respectively) but had decreased by 10 years (to 404+/-38 and 690+/-111 nm, respectively; P<0.001 and P=0.004 for the comparisons with the base-line values). The mesangial fractional volume (the proportion of the glomerulus occupied by the mesangium) increased from base line (0.33+/-0.07) to 5 years (0.39+/-0.10, P=0.02) but had decreased at 10 years (0.27+/-0.02, P=0.05 for the comparison with the baseline value and P=0.006 for the comparison with the value at 5 years), mostly because of a reduction in mesangial matrix. Pancreas transplantation can reverse the lesions of diabetic nephropathy, but reversal requires more than five years of normoglycemia.

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Intensified multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: the Steno type 2 randomised study.

H.-H. Parving, J P Vedel, O Pedersen … (1999)

In type 2 diabetes mellitus the aetiology of long-term complications is multifactorial. We carried out a randomised trial of stepwise intensive treatment or standard treatment of risk factors in patients with microalbuminuria. In this open, parallel trial patients were allocated standard treatment (n=80) or intensive treatment (n=80). Standard treatment followed Danish guidelines. Intensive treatment was a stepwise implementation of behaviour modification, pharmacological therapy targeting hyperglycaemia, hypertension, dyslipidaemia, and microalbuminuria. The primary endpoint was the development of nephropathy (median albumin excretion rate >300 mg per 24 h in at least one of the two-yearly examinations). Secondary endpoints were the incidence or progression of diabetic retinopathy and neuropathy. The mean age was 55.1 years (SD 7.2) and patients were followed up for 3.8 years (0.3). Patients in the intensive group had significantly lower rates of progression to nephropathy (odds ratio 0.27 [95% CI 0-10-0.75]), progression of retinopathy (0.45 [0.21-0.95]), and progression of autonomic neuropathy (0.32 [0.12-0.78]) than those in the standard group. Intensified multifactorial intervention in patients with type 2 diabetes and microalbuminuria slows progression to nephropathy, and progression of retinopathy and autonomic neuropathy. However, further studies are needed to establish the effect of intensified multifactorial treatment on macrovascular complications and mortality.

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Author and article information

Journal

Journal ID (publisher-id): NEE

Journal ID (nlm-ta): Nephron Exp Nephrol

Journal ID (doi): 10.1159/issn.1660-2129

Title: Cardiorenal Medicine

Publisher: S. Karger AG

ISSN (Electronic): 1660-2129

Publication date Subscription-year: 2007

Publication date (Print): January 2007

Publication date (Electronic): 30 November 2006

Volume: 105

Issue: 2

Pages: e45-e52

Affiliations

^aPharmacology Research Laboratories; ^bChemistry Research Laboratories, and ^cTechnology Research and Development Center, Chemical Synthesis Laboratories, Dainippon Sumitomo Pharma Co., Ltd, Drug Research Division, Osaka, Japan

Article

Publisher ID: 97603 Other ID: Nephron Exp Nephrol 2007;105:e45–e52

DOI: 10.1159/000097603

PubMed ID: 17139189

SO-VID: 9f09cfe4-f059-4e38-8d05-f1772bed3218

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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.

History

Date received : 20 March 2006

Date accepted : 25 August 2006

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Figures: 5, Tables: 1, References: 36, Pages: 1

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Amelioration of Established Diabetic Nephropathy by Combined Treatment with SMP-534 (Antifibrotic Agent) and Losartan in db/db Mice

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Karger: Nephrology

Most cited references 24

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.

Reversal of lesions of diabetic nephropathy after pancreas transplantation.

Intensified multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: the Steno type 2 randomised study.

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