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  5. Sirolimus enhances cyclosporine a-induced cytotoxicity in human renal glomerular mesangial cells
 
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Sirolimus enhances cyclosporine a-induced cytotoxicity in human renal glomerular mesangial cells

Author(s)
O'Connell, Séin  
Slattery, Craig  
Ryan, Michael P.  
McMorrow, Tara  
Uri
http://hdl.handle.net/10197/3596
Date Issued
2012-01-23
Date Available
2012-05-01T15:14:26Z
Abstract
End Stage Renal Disease (ESRD) is an ever increasing problem worldwide. However the mechanisms underlying disease progression are not fully elucidated. This work addressed the nephrotoxicity induced by the immunosuppressive agents’ cyclosporine
A (CsA) and sirolimus (SRL). Nephrotoxicity is the major limiting factor in the long
term use of CsA. SRL causes less nephrotoxicity than CsA. Therefore investigations into the differential effects of these agents may identify potential mechanisms of nephrotoxicity and possible means to prevent ESRD induced by therapeutic drugs. Using ELISA, western blotting, quantitative PCR and a reporter gene assay we
detailed the differential effects of the immunosuppressive agents CsA, and SRL in
human renal mesangial cells. CsA treatment increased profibrotic TGF-β1 secretion in
human mesangial cells whereas SRL did not, indicating a role for TGF-β in CsA toxicity. However we observed a synergistic nephrotoxic effect when CsA and SRL were co-administered. These synergistic alterations may have been due to an increase in CTGF which was not evident when the immunosuppressive drugs were used alone. The CsA/SRL combination therapy significantly enhanced Smad signalling and altered the extracellular matrix regulator matrix metalloproteinase 9 (MMP-9). Inhibition of the ERK 1/2 pathway, attenuated these CsA/SRL induced alterations indicating a potentially significant role for this pathway.
Sponsorship
Science Foundation Ireland
Higher Education Authority
Irish Research Council for Science, Engineering and Technology
Health Research Board
Other funder
Other Sponsorship
Enterprise Ireland
Type of Material
Journal Article
Publisher
Hindawi
Journal
Journal of Transplantation
Volume
2012
Copyright (Published Version)
2012 the authors
Subjects

Mesangial cell toxici...

Cyclosporine A

Subject – LCSH
Kidneys--Blood-vessels
Nephrotoxicology
Cyclosporine
Rapamycin
DOI
10.1155/2012/980910
Web versions
http://dx.doi.org/10.1155/2012/980910
Language
English
Status of Item
Peer reviewed
This item is made available under a Creative Commons License
https://creativecommons.org/licenses/by-nc-sa/1.0/
File(s)
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980910.pdf

Size

1.17 MB

Format

Adobe PDF

Checksum (MD5)

84b8de76a7d0f112f24a5c8b99b21263

Owning collection
Conway Institute Research Collection
Mapped collections
Biomolecular and Biomedical Science Research Collection

Item descriptive metadata is released under a CC-0 (public domain) license: https://creativecommons.org/public-domain/cc0/.
All other content is subject to copyright.

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