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      Call for Papers: Green Renal Replacement Therapy: Caring for the Environment

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      The Importance of Cellular VEGF Bioactivity in the Development of Glomerular Disease

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          Abstract

          The bioactivity of glomerular VEGF (or activity of available VEGF) is critical to the physiological maintenance of the glomerular filtration barrier. Disturbances in glomerular VEGF expression have been linked to numerous glomerulopathies, highlighting its importance in disease progression within the kidney. However, the changes in expression are not consistent between conditions; enhanced expression sometimes appears to have a renoprotective effect, yet at other times it appears destructive. Also, the level of expression can change with the progression of disease. This review focuses on how other cellular factors, such as TGF-β and nitric oxide, work in concert to affect the bioactivity, which is not necessarily the same as the expression of VEGF, in different glomerulopathies and attempts to explain some of the paradoxes between glomerulopathies. In conclusion, the bioactivity of glomerular VEGF is regulated by many factors that are themselves moderated by changes in the local glomerular environment, such as mechanical strain and hyperglycaemia. Thus, to understand VEGF signalling in glomerular disease progression, we must examine it in the context of other appropriate cellular factors.

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          Most cited references32

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          VEGF-A splicing: the key to anti-angiogenic therapeutics?

          The physiology of microvessels limits the growth and development of tumours. Tumours gain nutrients and excrete waste through growth-associated microvessels. New anticancer therapies target this microvasculature by inhibiting vascular endothelial growth factor A (VEGF-A) splice isoforms that promote microvessel growth. However, certain VEGF-A splice isoforms in normal tissues inhibit growth of microvessels. Thus, it is the VEGF-A isoform balance, which is controlled by mRNA splicing, that orchestrates angiogenesis. Here, we highlight the functional differences between the pro-angiogenic and the anti-angiogenic VEGF-A isoform families and the potential to harness the synthetic capacity of cancer cells to produce factors that inhibit, rather than aid, cancer growth.
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            Vascular endothelial growth factor signaling pathways: therapeutic perspective.

            The establishment of a vascular supply is one of the earliest and most important events occurring during embryonic development. Growth and maturation of a functional vascular network are complex and still incompletely understood processes involving orchestrated activation of vascular progenitors in the early stages of embryonic development followed by vasculogenesis and angiogenesis. These processes require a tightly regulated activation of several growth factors and their receptors. The role of vascular endothelial growth factors (VEGF) and their receptors has been studied extensively due to their prominent role during blood vessel formation. Mice deficient in various VEGF ligands or receptors show serious defects in vascular formation and maturation. Moreover, members of the VEGF family are involved in other significant biological processes, including lymphangiogenesis, vascular permeability, and hematopoiesis. Importantly, VEGF is released by tumor cells and induces tumor neovascularization. It is now well established that the VEGF axis represents an important target for antitumor therapy. Aberrant VEGF signaling is also a feature of several other pathologic conditions, such as age-related macular degeneration and rheumatoid arthritis.
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              VEGF165b, an inhibitory vascular endothelial growth factor splice variant: mechanism of action, in vivo effect on angiogenesis and endogenous protein expression.

              Growth of new blood vessels (angiogenesis), required for all tumor growth, is stimulated by the expression of vascular endothelial growth factor (VEGF). VEGF is up-regulated in all known solid tumors but also in atherosclerosis, diabetic retinopathy, arthritis, and many other conditions. Conventional VEGF isoforms have been universally described as proangiogenic cytokines. Here, we show that an endogenous splice variant, VEGF(165)b, is expressed as protein in normal cells and tissues and is circulating in human plasma. We also present evidence for a sister family of presumably inhibitory splice variants. Moreover, these isoforms are down-regulated in prostate cancer. We also show that VEGF(165)b binds VEGF receptor 2 with the same affinity as VEGF(165) but does not activate it or stimulate downstream signaling pathways. Moreover, it prevents VEGF(165)-mediated VEGF receptor 2 phosphorylation and signaling in cultured cells. Furthermore, we show, with two different in vivo angiogenesis models, that VEGF(165)b is not angiogenic and that it inhibits VEGF(165)-mediated angiogenesis in rabbit cornea and rat mesentery. Finally, we show that VEGF(165)b expressing tumors grow significantly more slowly than VEGF(165)-expressing tumors, indicating that a switch in splicing from VEGF(165) to VEGF(165)b can inhibit tumor growth. These results suggest that regulation of VEGF splicing may be a critical switch from an antiangiogenic to a proangiogenic phenotype.
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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
                2009
                August 2009
                09 July 2009
                : 113
                : 1
                : e8-e15
                Affiliations
                Academic Renal Unit, University of Bristol, Southmead Hospital, Bristol, UK
                Article
                228078 Nephron Exp Nephrol 2009;113:e8–e15
                10.1159/000228078
                19590237
                a772d1e2-4d95-4c72-896a-7e690ec3d10f
                © 2009 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.

                History
                Page count
                Figures: 1, References: 40, Pages: 1
                Categories
                Minireview

                Cardiovascular Medicine,Nephrology
                Vascular endothelial growth factor,Glomerular endothelial cells,Glomerulopathy,Diabetic nephropathy,Pre-eclampsia,Hypertension

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