Altered Expression of Matrix-Related Molecules in the Development of Chronic Thy1.1 Nephritis

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Abstract

Background/Aim: Matrix production and degradation are critically important in chronic nephritis. Our aim was to investigate the precise expression of matrix-related molecules which is essential for understanding the pathogenesis of renal disease. Methods: Chronic nephritis was induced by a single injection of anti-Thy1.1 antibody to unilaterally nephrectomized rats. RNA was extracted from renal cortex and isolated glomeruli 4, 7, and 10 weeks after the antibody injection. Matrix-related gene expressions were measured by polymerase chain reaction. The expression of α1(IV) and α3(IV) collagens was studied by immunohistochemistry. The gelatinolytic activity in the glomeruli was assayed by gelatin zymography. Results: Polymerase chain reaction revealed an increase of α1(IV) in both glomeruli and renal cortex from nephritic rats. In contrast, the expression of α3(IV), normally a component of the glomerular basement membrane, was decreased in nephritic animals. Immunohistochemistry confirmed the finding that α1(IV) and α3(IV) were up- and downregulated, respectively, in the glomeruli. Gene expression and activity of matrix metalloproteinase 2 were enhanced, while those of matrix metalloproteinase 9 were clearly suppressed in nephritis. Conclusions: Downregulation of α3(IV) and enhancement of the matrix metalloproteinase-2 activity in the glomeruli may contribute to the glomerular damage by altering the glomerular basement membrane components. Impairment of the glomerular basement membrane integrity may possibly be implicated in irreversible renal dysfunction.

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Most cited references 24

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Identification of mutations in the COL4A5 collagen gene in Alport syndrome.

Jun Zhou, James C L Chow, C Atkin … (1990)

X-linked Alport syndrome is a hereditary glomerulonephritis in which progressive loss of kidney function is often accompanied by progressive loss of hearing. Ultrastructural defects in glomerular basement membranes (GBM) of Alport syndrome patients implicate an altered structural protein as the cause of nephritis. The product of COL4A5, the alpha 5(IV) collagen chain, is a specific component of GBM within the kidney, and the gene maps to the same X chromosomal region as does Alport syndrome. Three structural aberrations were found in COL4A5, in intragenic deletion, a Pst I site variant, and an uncharacterized abnormality, which appear to cause nephritis and deafness, with allele-specific severity, in three Alport syndrome kindreds in Utah.

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Identification of mutations in the alpha 3(IV) and alpha 4(IV) collagen genes in autosomal recessive Alport syndrome.

Y Pirson, M Mariyama, C Verellen … (1994)

Alport syndrome (AS) is an hereditary disease of basement membranes characterized by progressive renal failure and deafness. Changes in the glomerular basement membrane (GBM) in AS suggest that the type IV collagen matrix, the major structural component of GBM, is disrupted. We recently isolated the genes for two type IV collagens, alpha 3(IV) and alpha 4(IV), that are encoded head-to-head on human chromosome 2. These chains are abundant in normal GBM but are sometimes absent in AS. We screened for mutations in families in which consanguinity suggested autosomal recessive inheritance. Homozygous mutations were found in alpha 3(IV) in two families and in alpha 4(IV) in two others, demonstrating that these chains are important in the structural integrity of the GBM and that there is an autosomal form of AS in addition to the previously-defined X-linked form.

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Renal basement membrane components.

Jonathan J. Miner (1999)

Renal basement membrane components. Basement membranes are specialized extracellular matrices found throughout the body. They surround all epithelia, endothelia, peripheral nerves, muscle cells, and fat cells. They play particularly important roles in the kidney, as demonstrated by the fact that defects in renal basement membranes are associated with kidney malfunction. The major components of all basement membranes are laminin, collagen IV, entactin/nidogen, and sulfated proteoglycans. Each of these describes a family of related proteins that assemble with each other in the extracellular space to form the basement membrane. Over the last few years, new basement membrane components that are expressed in the kidney have been discovered. Here, the major components and their localization in mature and developing renal basement membranes are described. In addition, the phenotypes of basement membrane component gene mutations, both naturally occurring and experimental, are discussed, as is the aberrant deposition of basement membrane proteins in the extracellular matrix in several renal diseases.

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Journal

Journal ID (publisher-id): NEE

Journal ID (nlm-ta): Nephron Exp Nephrol

Journal ID (doi): 10.1159/issn.1660-2129

Title: Cardiorenal Medicine

Publisher: S. Karger AG

ISSN (Electronic): 1660-2129

Publication date Subscription-year: 2006

Publication date (Print): November 2006

Publication date (Electronic): 10 October 2006

Volume: 104

Issue: 4

Pages: e169-e182

Affiliations

Discovery Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan

Article

Publisher ID: 96068 Other ID: Nephron Exp Nephrol 2006;104:e169–e182

DOI: 10.1159/000096068

PubMed ID: 17028444

SO-VID: f59b26ed-ee55-4d8f-b143-8fc658eb1aa5

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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

Date received : 05 August 2005

Date accepted : 07 April 2006

Page count

Figures: 8, Tables: 2, References: 40, Pages: 1

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Altered Expression of Matrix-Related Molecules in the Development of Chronic Thy1.1 Nephritis

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Abstract

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Karger: Nephrology

Most cited references 24

Identification of mutations in the COL4A5 collagen gene in Alport syndrome.

Identification of mutations in the alpha 3(IV) and alpha 4(IV) collagen genes in autosomal recessive Alport syndrome.

Renal basement membrane components.

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