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      Hepatocyte Growth Factor Gene Therapy Slows Down the Progression of Diabetic Nephropathy in db/db Mice

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          Abstract

          Background: Effect of hepatocyte growth factor (HGF) has scarcely been determined on diabetic nephropathy. Methods: Adenovirus encoding human HGF gene or LacZ gene (as the control) was injected into the hindlimb muscles of the C57BL/KsJ-db/db (db/db) mice at the age of 12 weeks, a model of genetic diabetes. Diabetic nephropathy was then evaluated at the age of 24 weeks. Results: The urine volume and albumin excretion progressively decreased in the control, whereas they remained unchanged in the HGF-treated group during the 12-week follow-up. The HGF gene therapy did not affect glucose metabolism. However, it resulted in a better renal function as evaluated by creatinine clearance (Ccr) than the control; Ccr was progressively worsened in controls (0.14 ± 0.02 liters/day) whereas unchanged in the HGF gene-treated group (0.38 ± 0.09 liters/day, p < 0.05). Kidneys of the HGF gene-treated mice showed glomeruli with greater area and cell population, smaller glomerular sclerotic index, and less fibrosis in both glomeruli and renal tubules, where apoptotic rate of glomerular endothelial cells and that of tubular epithelial cells were significantly decreased. TGF-β1 expression was significantly decreased in kidneys of the HGF gene-treated group. Finally, the HGF treatment significantly improved the long-term survival of db/db mice. Conclusions: The HGF gene delivery thus appeared to slow down the aggravation of diabetic nephropathy in db/db mice by attenuating progression from the hyperfiltration phase into the sclerotic phase through antiapoptotic and antifibrotic actions. The present findings suggest that the HGF gene delivery can be a novel therapeutic approach against diabetic nephropathy.

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          Most cited references 23

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          Transforming growth factor beta in tissue fibrosis.

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            Molecular cloning and expression of human hepatocyte growth factor.

            Hepatocyte growth factor (HGF) is the most potent mitogen for mature parenchymal hepatocytes in primary culture, and seems to be a hepatotrophic factor that acts as a trigger for liver regeneration after partial hepatectomy and liver injury. The partial purification and characterization of HGF have been reported. We have demonstrated that pure HGF from rat platelets is a new growth factor effective at concentrations as low as 1 ng ml-1. The effects of HGF and epidermal growth factor (EGF) are additive. The activity of HGF is not species-specific, although it does not stimulate growth in Swiss 3T3 fibroblasts. HGF has a relative molecular mass (Mr) of 82,000 and is a heterodimer composed of a large alpha-subunit of Mr 69,000 and a small beta-subunit of Mr 34,000. Here we report the amino-acid sequence of human HGF determined by complementary DNA cloning and the expression of biologically active human HGF from COS-1 cells transfected with cloned cDNA. The nucleotide sequence of the human HGF cDNA reveals that both alpha- and beta-chains are contained in a single open reading frame coding for a pre-pro precursor protein of 728 amino acids.
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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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                Author and article information

                Journal
                NEP
                Nephron Physiol
                10.1159/issn.1660-2137
                Nephron Physiology
                S. Karger AG
                1660-2137
                2006
                February 2006
                23 February 2006
                : 102
                : 3-4
                : p92-p102
                Affiliations
                Departments of aInternal Medicine, bGene Therapy and Regenerative Medicine, and cOriental Medicine, Gifu University School of Medicine, Gifu; dDepartment of Food Science, Kyoto Women’s University, Kyoto, and eDivision of Nephrology, Gifu Prefectural Gifu Hospital, Gifu, Japan
                Article
                90071 Nephron Physiol 2006;102:p92–p102
                10.1159/000090071
                16340242
                © 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: 8, Tables: 1, References: 38, Pages: 1
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/90071
                Categories
                Original Paper

                Cardiovascular Medicine, Nephrology

                Growth factors, Nephropathy, Diabetes, Gene therapy, Apoptosis

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