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

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      Transgenic Models in Renal Tubular Physiology

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          Abstract

          Animal transgenesis has proven to be useful for physiological as well as physiopathological studies. Besides the classical approach based on the random integration of a DNA construct in the mouse genome, gene targeting can be achieved using totipotent embryonic stem (ES) cells for targeted transgenesis. Transgenic mice are then derived from the transgenic ES cells. This allows the introduction of null mutations in the genome (so-called knock-out) or the control of the transgene expression by the endogenous regulatory sequences of the gene of interest (so-called knock-in). Development of these transgenic animals leads to a better understanding of the cellular function of many genes or to the generation of animal models for human diseases. The purpose of this short review is to describe animal models in renal tubular physiopathology. Recent progresses will allow the generation of animal models with conditional expression of the transgene of interest or with a conditional gene mutation. This permits spatial and temporal control of the expression of the transgene or of the mutation. This should allow the generation of models suitable for physiological analysis or closer to disease state.

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          Most cited references8

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          Control of memory formation through regulated expression of a CaMKII transgene.

          One of the major limitations in the use of genetically modified mice for studying cognitive functions is the lack of regional and temporal control of gene function. To overcome these limitations, a forebrain-specific promoter was combined with the tetracycline transactivator system to achieve both regional and temporal control of transgene expression. Expression of an activated calcium-independent form of calcium-calmodulin-dependent kinase II (CaMKII) resulted in a loss of hippocampal long-term potentiation in response to 10-hertz stimulation and a deficit in spatial memory, a form of explicit memory. Suppression of transgene expression reversed both the physiological and the memory deficit. When the transgene was expressed at high levels in the lateral amygdala and the striatum but not other forebrain structures, there was a deficit in fear conditioning, an implicit memory task, that also was reversible. Thus, the CaMKII signaling pathway is critical for both explicit and implicit memory storage, in a manner that is independent of its potential role in development.
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            Autosomal dominant polycystic kidney disease.

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              Bartter's syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2.

              Inherited hypokalaemic alkalosis with low blood pressure can be divided into two groups-Gitelman's syndrome, featuring hypocalciuria, hypomagnesaemia and milder clinical manifestations, and Bartter's syndrome, featuring hypercalciuria and early presentation with severe volume depletion. Mutations in the renal Na-Cl cotransporter have been shown to cause Gitelman's syndrome. We demonstrate linkage of Bartter's syndrome to the renal Na-K-2Cl cotransporter gene NKCC2, and identify frameshift or non-conservative missense mutations for this gene that co-segregate with the disease. These findings demonstrate the molecular basis of Bartter's syndrome, provide the basis for molecular classification of patients with inherited hypokalaemic alkalosis, and suggest potential phenotypes in heterozygous carriers of NKCC2 mutations.
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                Author and article information

                Journal
                EXN
                Nephron Exp Nephrol
                10.1159/issn.1660-2129
                Cardiorenal Medicine
                S. Karger AG
                978-3-8055-6765-7
                978-3-318-00352-9
                1660-2129
                1998
                October 1998
                11 September 1998
                : 6
                : 5
                : 438-446
                Affiliations
                Institut National de la Santé et de la Recherche Médicale, U478, Faculté de Médecine Xavier-Bichat, Université Paris VII, Paris, France
                Article
                20553 Exp Nephrol 1998;6:438–446
                10.1159/000020553
                9fc5f8c3-2939-4118-99af-4baac5bf83f3
                © 1998 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: 2, Tables: 1, References: 52, Pages: 9
                Categories
                Genetically Modified Kidneys and Nephron Function

                Cardiovascular Medicine,Nephrology
                Conditional transgene expression,Homologous recombination,Transgenesis,Physiology,Biological sciences

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