Identification of novel indicators of cyclosporine A nephrotoxicity in a CD-1 mouse model

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Title: Identification of novel indicators of cyclosporine A nephrotoxicity in a CD-1 mouse model
Authors: O'Connell, Séin
Slattery, Craig
Ryan, Michael P.
McMorrow, Tara
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Date: 15-Apr-2011
Abstract: The calcineurin inhibitor cyclosporine A (CsA) is a widely used immunosuppressive agent. However,nephrotoxicity is a serious side effect observed in patients which limits clinical use of CsA. CsA nephrotoxicity is associated with tubulointerstitial injury progressing to nephropathy. This is typically diagnosed by invasive renal biopsy and is often only detected when the disease process is well advanced. Therefore identification of novel, early indicators of CsA nephrotoxicity could be clinically advantageous. This study aimed to establish a murine model of CsA nephrotoxicity and to identify urinary proteins that may indicate the onset of CsAinduced nephropathy using 2-D gel electrophoresis. CsA nephrotoxicity was induced in CD-1 mice by daily CsA administration for 4 weeks. By week 4, elevated serum creatinine and proteinuria were observed after CsA treatment indicating significant renal dysfunction. Decreased cadherin-1, increased α-smooth muscle actin and fibroblast specific protein 1 in kidney tissue indicated disruption of normal tubular architecture. Alterations in podocin and uromodulin were also observed which may indicate damage to other segments of the nephron. Proteomic analysis of urine identified a number of differentially regulated proteins that may be involved in early CsA nephropathy including cadherin 1, superoxide dismutase and vinculin. These findings suggest novel mechanisms of CsA nephrotoxicity and identify novel potential markers of the disease.
Funding Details: Science Foundation Ireland
Higher Education Authority
Irish Research Council for Science, Engineering and Technology
European Research Council
Health Research Board
Type of material: Journal Article
Publisher: Elsevier
Journal: Toxicology and Applied Pharmacology
Volume: 252
Issue: 2
Start page: 201
End page: 210
Copyright (published version): 2011 Elsevier Inc.
Keywords: Cadherin 1 (CDH-1)Fibroblast specific protein 1Transforming growth factor beta 1 and 2-DEConnective tissue growth factor
Subject LCSH: Cadherins
Connective tissues--Growth
Fibroblast growth factors
Transforming growth factors
DOI: 10.1016/j.taap.2011.02.015
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Language: en
Status of Item: Peer reviewed 2011-04-04T10:06:59Z
Appears in Collections:Conway Institute Research Collection
Biomolecular and Biomedical Science Research Collection

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