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      Tandem Repeats Polymorphism of MUC20 Is an Independent Factor for the Progression of Immunoglobulin A Nephropathy

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          Abstract

          MUC20, an upregulated novel gene in the renal tissues of patients with IgA nephropathy (IgAN), was recently identified. The variable number of tandem repeats (VNTR) polymorphism of the MUC20 gene was detected in several cell lines. In the present study, we investigated a possible association of MUC20 VNTR polymorphism with the clinical manifestations and progression in patients with IgAN. A total of 1,147 Chinese subjects, including 657 patients with IgAN and 490 geographically matched healthy controls, were involved in this investigation. One hundred and thirty-seven patients had been followed up for 60.6 ± 22.4 months. MUC20 VNTR polymorphism was genotyped by polymerase chain reaction amplification and confirmed by sequencing. The alleles were divided into two groups according to the repeat times of MUC20 VNTR, i.e. small alleles (VNTR repeat times ≤3) and large alleles (VNTR repeat times >3), and the genotypes of subjects were classified into SS, SL and LL groups. The frequencies of the alleles and genotypes of MUC20 VNTR polymorphisms did not differ between patients with IgAN and healthy controls. Additionally, there was no significant difference in the clinical features. Furthermore, IgAN patients with SL/LL genotypes had a higher risk of decline in renal function (odds ratio 20.9; 95% confidence interval 2.6–168.1; p = 0.004) than those with SS genotypes. The present study revealed that there is no association between the VNTR polymorphism of the MUC20 gene and the clinical manifestations in IgAN patients at the time of renal biopsy. However, IgAN patients with SL/LL genotypes had a higher risk of the progression to end-stage renal disease.

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          Most cited references 19

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          Mucins in cancer: protection and control of the cell surface.

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            Kidney injury molecule-1 (KIM-1), a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain, is up-regulated in renal cells after injury.

            We report the identification of rat and human cDNAs for a type 1 membrane protein that contains a novel six-cysteine immunoglobulin-like domain and a mucin domain; it is named kidney injury molecule-1 (KIM-1). Structurally, KIM-1 is a member of the immunoglobulin gene superfamily most reminiscent of mucosal addressin cell adhesion molecule 1 (MAdCAM-1). Human KIM-1 exhibits homology to a monkey gene, hepatitis A virus cell receptor 1 (HAVcr-1), which was identified recently as a receptor for the hepatitis A virus. KIM-1 mRNA and protein are expressed at a low level in normal kidney but are increased dramatically in postischemic kidney. In situ hybridization and immunohistochemistry revealed that KIM-1 is expressed in proliferating bromodeoxyuridine-positive and dedifferentiated vimentin-positive epithelial cells in regenerating proximal tubules. Structure and expression data suggest that KIM-1 is an epithelial cell adhesion molecule up-regulated in the cells, which are dedifferentiated and undergoing replication. KIM-1 may play an important role in the restoration of the morphological integrity and function to postischemic kidney.
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              Kidney injury molecule-1: a tissue and urinary biomarker for nephrotoxicant-induced renal injury.

              Nephrotoxicity is a common side effect of therapeutic interventions, environmental insults, and exposure to toxicants in the workplace. Although biomarkers for nephrotoxicity are available, they often lack sensitivity and are not specific as indicators of epithelial cell injury. Kidney injury molecule-1 (Kim-1) is a type 1 membrane protein with extracellular immunoglobulin and mucin domains. The mRNA and protein for Kim-1 are expressed at very low levels in normal rodent kidney, but expression increases dramatically after injury in proximal tubule epithelial cells in postischemic rodent kidney and in humans during ischemic acute renal failure. To evaluate the utility of Kim-1 as a biomarker for other types of renal injury, we analyzed tissue and urinary expression in response to three different types of nephrotoxicants in the rat: S-(1,1,2,2-tetrafluoroethyl)-l-cysteine (TFEC), folic acid, and cisplatin. Marked increases in Kim-1 expression were confirmed by immunoblotting in all three models. The protein was shown to be localized to the proximal tubule epithelial cell by immunofluorescence. Furthermore, Kim-1 protein was detected in urine of toxicant-treated rats. The temporal pattern of expression in response to TFEC is similar to the Kim-1 expression pattern in the postischemic kidney. In folic acid-treated kidneys, Kim-1 is clearly localized to the apical brush border of the well-differentiated proximal tubular epithelial cells. After folic acid treatment, expression of Kim-1 is present in the urine despite no significant increase in serum creatinine. Cisplatin treatment results in early detection of urinary Kim-1 protein and diffuse Kim-1 expression in S3 cells of the proximal tubule. Kim-1 can be detected in the tissue and urine on days 1 and 2 after cisplatin administration, occurring before an increase in serum creatinine. The upregulation of expression of Kim-1 and its presence in the urine in response to exposure to various types of nephrotoxicants suggest that this protein may serve as a general biomarker for tubular injury and repair processes.
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                Author and article information

                Journal
                AJN
                Am J Nephrol
                10.1159/issn.0250-8095
                American Journal of Nephrology
                S. Karger AG
                0250-8095
                1421-9670
                2006
                April 2006
                05 April 2006
                : 26
                : 1
                : 43-49
                Affiliations
                Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China
                Article
                91785 Am J Nephrol 2006;26:43–49
                10.1159/000091785
                16508246
                © 2006 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: 4, Tables: 4, References: 25, Pages: 7
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/91785
                Categories
                Original Report: Laboratory Investigation

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