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      • Record: found
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      • Article: found

      Genes and Proteins in Renal Development

      ,

      Cardiorenal Medicine

      S. Karger AG

      Ret, FGF, Integrin, BMP, Kidney development, Nephrogenesis, Genes, kidney development, Wnt

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          Abstract

          Metanephric kidney development begins with the formation of the metanephrogenic mesenchyme; this event depends on the prior action in the intermediate mesoderm of transcription factors such as Lim-1, Pax-2, Eya-1, and Foxc-1. Once it has formed, the mesenchyme secretes GDNF; this induces the nearby wolffian duct to produce a ureteric bud which invades the metanephrogenic mesenchyme and begins to arborize. Ureteric bud development and branching depends on the transcription factor Emx-2, the GDNF-cRet and probably the HGF/cMet, signalling systems, and the intracellular regulatory molecules formin IV and timeless. Proteins of the BMP family modulate ureteric bud branching and keep bud development in step with that of other tissue types. Proteins and glycosaminoglycans of the matrix, and their receptors, and also required. The metanephrogenic mesenchyme has a default fate of apoptosis and is dissuaded from suicide by factors secreted from the bud such as TGF-α, TIMP-2, EGF, and FGF-2. Other factors such as LIF and TGFβ2 cooperate with these to induce clumps of mesenchyme cells to differentiate into nephrons, while BMP-7 appears to lead them instead to form stroma. As nephrons form, they express critical transcription factors such as WT-1, Pax-2, and Hoxa11 and d11, condense, and secrete Wnt-4. Wnt-4 acts in an autocrine loop to stimulate its own synthesis and is required for cells to differentiate into epithelia; its action is antagonized by sFRP-1, secreted by stroma, but this antagonism is itself inhibited by sFRP-2 made by the developing nephron. This system probably acts both to limit the spread of Wnt-4’s influence and also to commit responding cells to their epithelial fate. As nephrons mature, regions of them differentiate to perform specific physiological functions, a process that requires the proteins WT-1, Lmx-1b, Notch-2, Jagged-1, and Hnf-1.

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          Most cited references 20

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          WT-1 is required for early kidney development.

          In humans, germline mutations of the WT-1 tumor suppressor gene are associated with both Wilms' tumors and urogenital malformations. To develop a model system for the molecular analysis of urogenital development, we introduced a mutation into the murine WT-1 tumor suppressor gene by gene targeting in embryonic stem cells. The mutation resulted in embryonic lethality in homozygotes, and examination of mutant embryos revealed a failure of kidney and gonad development. Specifically, at day 11 of gestation, the cells of the metanephric blastema underwent apoptosis, the ureteric bud failed to grow out from the Wolffian duct, and the inductive events that lead to formation of the metanephric kidney did not occur. In addition, the mutation caused abnormal development of the mesothelium, heart, and lungs. Our results establish a crucial role for WT-1 in early urogenital development.
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            Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4.

            The kidney has been widely exploited as a model system for the study of tissue inductions regulating vertebrate organogenesis. Kidney development is initiated by the ingrowth of the Wolfian duct-derived ureteric bud into the presumptive kidney mesenchyme. In response to a signal from the ureter, mesenchymal cells condense, aggregate into pretubular clusters and undergo an epithelial conversion generating a simple tubule. This then undergoes morphogenesis and is transformed into the excretory system of the kidney, the nephron. We report here that the expression of Wnt-4, which encodes a secreted glycoprotein, correlates with, and is required for, kidney tubulogenesis. Mice lacking Wnt-4 activity fail to form pretubular cell aggregates; however, other aspects of mesenchymal and ureteric development are unaffected. Thus, Wnt-4 appears to act as an autoinducer of the mesenchyme to epithelial transition that underlies nephron development.
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              Vascular Endothelial Growth Factor Induces Endothelial Fenestrations In Vitro

              Abstract. Vascular endothelial growth factor (VEGF) is an important regulator of vasculogenesis, angiogenesis, and vascular permeability. In contrast to its transient expression during the formation of new blood vessels, VEGF and its receptors are continuously and highly expressed in some adult tissues, such as the kidney glomerulus and choroid plexus. This suggests that VEGF produced by the epithelial cells of these tissues might be involved in the induction or maintenance of fenestrations in adjacent endothelial cells expressing the VEGF receptors. Here we describe a defined in vitro culture system where fenestrae formation was induced in adrenal cortex capillary endothelial cells by VEGF, but not by fibroblast growth factor. A strong induction of endothelial fenestrations was observed in cocultures of endothelial cells with choroid plexus epithelial cells, or mammary epithelial cells stably transfected with cDNAs for VEGF 120 or 164, but not with untransfected cells. These results demonstrate that, in these cocultures, VEGF is sufficient to induce fenestrations in vitro. Identical results were achieved when the epithelial cells were replaced by an epithelial-derived basal lamina-type extracellular matrix, but not with collagen alone. In this defined system, VEGF-mediated induction of fenestrae was always accompanied by an increase in the number of fused diaphragmed caveolae-like vesicles. Caveolae, but not fenestrae, were labeled with a caveolin-1–specific antibody both in vivo and in vitro. VEGF stimulation led to VEGF receptor tyrosine phosphorylation, but no change in the distribution, phosphorylation, or protein level of caveolin-1 was observed. We conclude that VEGF in the presence of a basal lamina-type extracellular matrix specifically induces fenestrations in endothelial cells. This defined in vitro system will allow further study of the signaling mechanisms involved in fenestrae formation, modification of caveolae, and vascular permeability.
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                Author and article information

                Journal
                EXN
                Nephron Exp Nephrol
                10.1159/issn.1660-2129
                Cardiorenal Medicine
                S. Karger AG
                978-3-8055-7383-2
                978-3-318-00822-7
                1660-2129
                2002
                2002
                05 April 2002
                : 10
                : 2
                : 102-113
                Affiliations
                Centre for Developmental Biology, Edinburgh University Medical School, Edinburgh, UK
                Article
                49905 Exp Nephrol 2002;10:102–113
                10.1159/000049905
                11937757
                © 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: 2, References: 96, Pages: 12
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/49905
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