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      T -786→C Polymorphism of the Endothelial Nitric Oxide Synthase Gene Influences the Progression of Renal Disease

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          Abstract

          Background/Aims: Polymorphism of the endothelial nitric oxide synthase (ecNOS) gene may be involved in renal disease. Recently, T<sup>-786</sup>→C polymorphism affecting ecNOS gene transcription has been reported. To clarify the role of T<sup>-786</sup>→C polymorphism in renal disease, we investigated hemodialysis patients and healthy controls for this polymorphism and we compared its frequency with that of intron 4 polymorphism in the hemodialysis patients. Methods: The subjects were 252 patients who had been on hemodialysis for less than 2 years (168 with nondiabetic nephropathy and 84 with diabetic nephropathy) and 187 healthy controls. T<sup>-786</sup>→C polymorphism was detected using polymerase chain reaction-restriction fragment length polymorphism analysis. Results: The frequencies of the T/ C and C/ C genotypes were significantly higher in the nondiabetic hemodialysis patients than in the controls (odds ratio 1.41; 95% Cl 1.03–2.00), and were also significantly higher in the diabetic hemodialysis patients than in the controls (odds ratio 1.56; 95% Cl 1.02–2.41). In addition, T<sup>-786</sup>→C polymorphism and intron 4 polymorphism showed strong linkage disequilibrium. Conclusion: T<sup>-786</sup>→C polymorphism may be involved in the progression of both nondiabetic and diabetic nephropathy, along with intron 4 polymorphism.

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            Gene structure, polymorphism and mapping of the human endothelial nitric oxide synthase gene.

            Endothelium-derived relaxing factor (EDRF)/nitric oxide (NO) is synthesized from L-Arginine by the endothelial, constitutive, NO synthase. No facilitate genetic studies, we have cloned the human endothelial NO synthase gene and determined its structure. The gene is composed of 26 exons, ranging from 68 to 579 bp and spans 22 kb. We determined the transcription start point using human lung mRNA. No TATA-box was found at the expected distance from the transcription start point and several consensus sequences for transcription factors, including a shear-stress responsive element were identified in the 5'-flanking region. A highly polymorphic (CA) repeat within intron 13 was studied, allowing the precise genetic mapping of the gene to chromosome 7, within a 4 cM interval delimited by genethon markers AFM199Zd4 and AFM074Xg5.
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              Nitric oxide modulates the synthesis of extracellular matrix proteins in cultured rat mesangial cells.

              Nitric oxide (NO) is an important effector molecule of the inflammatory response. It is synthesized by mesangial cells and has been proposed to contribute to glomerular injury in various disease states. We studied whether NO modulates extracellular matrix production in cultured rat mesangial cells. Stimulation of rat mesangial cell NO release with gamma-interferon and lipopolysaccharide resulted in reduced production of collagen (by 35%) fibronectin (by 48%) (P < 0.05). In contrast, laminin synthesis was enhanced two-fold by the same maneuver (P < 0.05). These changes were reversed by the addition of L-NAME, a selective inhibitor of inducible nitric oxide synthase. This is the first demonstration that NO regulates the synthesis of extracellular matrix by mesangial cells. The results indicate that increased renal production of NO in glomerular diseases may attenuate the production and accumulation of matrix proteins and limit the severity of glomerulosclerosis.
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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
                August 2002
                15 July 2002
                : 91
                : 4
                : 747-751
                Affiliations
                Second Department of Internal Medicine, Hiroshima University School of Medicine, Hiroshima, Japan
                Article
                65041 Nephron 2002;91:747–751
                10.1159/000065041
                12138283
                2a9857e1-3b2e-4dee-9d60-6fbfcf94a459
                © 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.

                History
                Page count
                Figures: 1, Tables: 2, References: 19, Pages: 5
                Categories
                Short Communication

                Cardiovascular Medicine,Nephrology
                Nondiabetic nephropathy,Endothelial nitric oxide synthase,Gene polymorphism,End-stage renal disease,Diabetic nephropathy

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