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      Hepatocyte Growth Factor-Stimulating Endothelial Cell Growth and Accelerating Glomerular Capillary Repair in Experimental Progressive Glomerulonephritis

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          Abstract

          Hepatocyte growth factor (HGF) is one of the major growth factors that stimulate the growth and the migration of vascular endothelial cells. In this study, we examined the beneficial effects of HGF for glomerular repair in an experimental progressive glomerulonephritis (GN) model prepared by injecting both anti-Thy-1.1 antibody (day 0) and habu-snake venom (day 1) in rats. The rats received continuous intraperitoneal administration of recombinant human HGF (80 µg/100 g/day) or vehicle control at an early stage (day 2 to day 9), after severe glomerular injury. The vehicle-infused control rats initially showed severe mesangiolysis with large ballooning (day 2), followed by the prominent proliferation of mesangial cells with minimal capillary regeneration (day 5 to week 2), and global sclerosis with chronic renal failure (week 4 to week 8). Although mesangiolysis with large ballooning and mesangial cell proliferation were also observed in the HGF-infused rats, glomerular capillary regeneration with marked endothelial cell proliferation occurred during HGF administration from day 2 to day 9. Subsequently, the glomerulus was repaired with the development of the capillary network and the reduction of mesangial hypercellularity from week 2 to week 4, and almost all of the glomeruli showed a normal structure by week 8. The HGF-treated rats showed significantly better renal functions (Cr: 0.3 ± 0.1 vs. 3.5 ± 1.1 mg/dl in control, p < 0.001), less proteinuria (21.2 ± 8.0 mg/day vs. 421.4 ± 45.1 mg/day in control, p < 0.001) and less glomerular sclerosis at week 8 than the vehicle-infused rats. We conclude that HGF accelerated glomerular repair through the growth of capillary endothelial cells and capillary regeneration in experimental progressive GN. Administering HGF is a logical and efficient strategy for treating progressive GN with severe capillary destruction.

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          Most cited references 7

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          Transforming growth factor beta in tissue fibrosis.

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            Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth

            Hepatocyte Growth Factor (HGF, also known as Scatter Factor) is a powerful mitogen or motility factor in different cells, acting through the tyrosine kinase receptor encoded by the MET protooncogene. Endothelial cells express the MET gene and expose at the cell surface the mature protein (p190MET) made of a 50 kD (alpha) subunit disulfide linked to a 145-kD (beta) subunit. HGF binding to endothelial cells identifies two sites with different affinities. The higher affinity binding site (Kd = 0.35 nM) corresponds to the p190MET receptor. Sub- nanomolar concentrations of HGF, but not of a recombinant inactive precursor, stimulate the receptor kinase activity, cell proliferation and motility. HGF induces repairs of a wound in endothelial cell monolayer. HGF stimulates the scatter of endothelial cells grown on three-dimensional collagen gels, inducing an elongated phenotype. In the rabbit cornea, highly purified HGF promotes neovascularization at sub-nanomolar concentrations. HGF lacks activities related to hemostasis-thrombosis, inflammation and endothelial cells accessory functions. These data show that HGF is an in vivo potent angiogenic factor and in vitro induces endothelial cells to proliferate and migrate.
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              Purification and subunit structure of hepatocyte growth factor from rat platelets.

              A hepatocyte growth factor (HGF) that stimulates DNA synthesis of adult rat hepatocytes in primary culture was purified as a homogeneous material from platelets of 1000 rats by a four-step procedure: stimulation of its release from platelets by thrombin, cation-exchanger fast protein liquid chromatography (FPLC) on a Mono S column, heparin-Sepharose CL-6B chromatography, and reverse-phase HPLC on a C4 column. The purified HGF stimulated DNA synthesis of adult rat hepatocytes in primary culture at 1 ng/ml and was maximally effective at 5 ng/ml, being about twice as potent as EGF at this concentration. HGF did not stimulate DNA synthesis of Swiss 3T3 cells. It was found to be a heat- and acid-labile protein that was inactivated by reduction with dithiothreitol. The purified HGF had a molecular mass of 82 kDa, as estimated by SDS-PAGE, and was found to be a heterodimer which dissociated into a large subunit of 69 kDa and a small one of 34 kDa by SDS-PAGE under reducing conditions. These biological and chemical properties showed that HGF was not identical with any known growth factors, including platelet-derived growth factor (PDGF).
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                Author and article information

                Journal
                NEE
                Nephron Exp Nephrol
                10.1159/issn.1660-2129
                Cardiorenal Medicine
                S. Karger AG
                1660-2129
                2003
                June 2003
                17 November 2004
                : 94
                : 2
                : e44-e54
                Affiliations
                Department of Pathology, Nippon Medical School, Tokyo, Japan
                Article
                71283 Nephron Exp Nephrol 2003;94:e44–e54
                10.1159/000071283
                12845230
                © 2003 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: 13, References: 34, Pages: 1
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/71283
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