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      Downregulation of Vascular Endothelial Growth Factor and Its Receptors in the Kidney in Rats with Puromycin Aminonucleoside Nephrosis

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          Abstract

          Aim: We aimed to examine the possible involvement of vascular endothelial growth factor (VEGF) in the pathogenesis of puromycin aminonucleoside nephrosis (PAN). Methods: The expression and localization of the mRNA of VEGF and its receptors, flt-1 and flk-1, were analyzed in the kidneys of puromycin aminonucleoside-injected rats by use of Northern blotting and in situ hybridization. Results: In association with the induction of proteinuria, VEGF mRNA underwent decrease in amount from 3 days after the injection, reaching the minimum level at 7 days, followed by a gradual recovery by 28 days. The levels of flk-1 and flt-1 mRNA showed similar transient decrease in PAN kidney, whereas the mRNA of von Willebrand factor, a marker of endothelial cells, showed no change in amount. In the normal rat kidney, VEGF mRNA was localized primarily to podocytes, and flk-1 mRNA was localized exclusively to endothelial cells with much higher intensity in glomeruli than in peritubular capillaries. In PAN kidney, the intensities of both VEGF and flk-1 signals in podocytes and glomerular endothelial cells, respectively, appeared much lower at 7 days than in normal kidney. Conclusion: These results indicate that the VEGF-VEGF receptor system is downregulated in PAN, implying that it is not involved in the mechanism of proteinuria in PAN.

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          Most cited references 4

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          Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction.

          A new method of total RNA isolation by a single extraction with an acid guanidinium thiocyanate-phenol-chloroform mixture is described. The method provides a pure preparation of undegraded RNA in high yield and can be completed within 4 h. It is particularly useful for processing large numbers of samples and for isolation of RNA from minute quantities of cells or tissue samples.
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            Homeostatic modulation of cell surface KDR and Flt1 expression and expression of the vascular endothelial cell growth factor (VEGF) receptor mRNAs by VEGF.

             R Warren,  Z. Wang,  D B Donner (2000)
            Vascular endothelial cell growth factor (VEGF) is a potent angiogenic factor expressed during embryonic development, during wound healing, and in pathologies dependent on neovascularization, including cancer. Regulation of the receptor tyrosine kinases, KDR and Flt-1, to which VEGF binds on endothelial cells is incompletely understood. Chronic incubation with tumor-conditioned medium or VEGF diminished (125)I-VEGF binding to human umbilical vein endothelial cells, incorporation of (125)I-VEGF into covalent complexes with KDR and Flt1, and immunoreactive KDR in cell lysates. Receptor down-regulation desensitized VEGF activation of mitogen-activated protein kinase (extracellular signal-regulated kinases 1 and 2) and p38 mitogen-activated protein kinase. Preincubation with VEGF or tumor-conditioned medium down-regulated cell surface receptor expression but up-regulated KDR and Flt-1 mRNAs, an effect abrogated by a neutralizing VEGF antibody. Removal of VEGF from the medium led to recovery of (125)I-VEGF binding and resensitization of human umbilical vein endothelial cells. Recovery of receptor expression was inhibited by cycloheximide, indicating that augmented VEGF receptor mRNAs, and not receptor recycling from a cytoplasmic pool, restored responsiveness. As the VEGF receptors promote endothelial cell survival, proliferation, and other events necessary for angiogenesis, the noncoordinate regulation of VEGF receptor proteins and mRNAs suggests that human umbilical vein endothelial cells are protected against inappropriate or prolonged loss of VEGF receptors by a homeostatic mechanism important to endothelial cell function.
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              Two functional forms of vascular endothelial growth factor receptor-2/Flk-1 mRNA are expressed in normal rat retina.

              Vascular endothelial growth factor (VEGF) is an important mediator of ocular neovascularization by exerting its endothelial specific mitogenic effects through high affinity tyrosine kinase receptors. By screening a rat retina cDNA library, we have isolated a clone encoding the full-length prototypic form of the rat VEGF receptor-2/Flk-1, as well as a short form of the mRNA that encodes the complete seven N-terminal immunoglobulin-like extracellular ligand-binding domains, transmembrane region, NH2-terminal half of the intracellular kinase domain, and kinase insert domain but does not encode the COOH-terminal half of the intracellular kinase domain and carboxyl-terminal region. Both forms of mRNA are detected in rat retina, although the short form is expressed at a lower level. VEGF induced a biphasic increase of cytoplasmic calcium with both forms in HK 293 transfected cells, indicating that both forms of the VEGF receptor-2/Flk-1 are functional and that the COOH-terminal half of the intracellular kinase domain and carboxyl region of VEGF receptor-2/Flk-1 are not strictly necessary for either ligand binding or this biological activity.
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                Author and article information

                Journal
                NEF
                Nephron
                10.1159/issn.1660-8151
                Nephron
                S. Karger AG
                1660-8151
                2235-3186
                2002
                2002
                13 December 2001
                : 90
                : 1
                : 95-102
                Affiliations
                Departments of aAnatomy and bBiophysical Genetics, School of Medicine, Kanazawa University, Kanazawa, Japan
                Article
                46320 Nephron 2002;90:95–102
                10.1159/000046320
                11744811
                © 2002 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, References: 39, Pages: 8
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/46320
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