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

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dc.contributor.author O'Connell, Séin
dc.contributor.author Slattery, Craig
dc.contributor.author Ryan, Michael P.
dc.contributor.author McMorrow, Tara
dc.date.accessioned 2012-05-01T15:14:26Z
dc.date.available 2012-05-01T15:14:26Z
dc.date.copyright 2012 the authors en
dc.date.issued 2012-01-23
dc.identifier.citation Journal of Transplantation en
dc.identifier.uri http://hdl.handle.net/10197/3596
dc.description.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. en
dc.description.sponsorship Science Foundation Ireland en
dc.description.sponsorship Higher Education Authority en
dc.description.sponsorship Irish Research Council for Science, Engineering and Technology en
dc.description.sponsorship Health Research Board en
dc.description.sponsorship Other funder en
dc.format.extent 1226423 bytes
dc.format.mimetype application/pdf
dc.language.iso en en
dc.publisher Hindawi en
dc.relation.requires Biomolecular and Biomedical Science Research Collection en
dc.subject Mesangial cell toxicity en
dc.subject Cyclosporine A en
dc.subject.lcsh Kidneys--Blood-vessels en
dc.subject.lcsh Nephrotoxicology en
dc.subject.lcsh Cyclosporine en
dc.subject.lcsh Rapamycin en
dc.title Sirolimus enhances cyclosporine a-induced cytotoxicity in human renal glomerular mesangial cells en
dc.type Journal Article en
dc.internal.availability Full text available en
dc.internal.webversions Publisher's version en
dc.internal.webversions http://dx.doi.org/10.1155/2012/980910 en
dc.status Peer reviewed en
dc.identifier.volume 2012 en
dc.citation.other Article ID 980910 en
dc.identifier.doi 10.1155/2012/980910
dc.neeo.contributor O'Connell|Séin|aut| en
dc.neeo.contributor Slattery|Craig|aut| en
dc.neeo.contributor Ryan|Michael P.|aut| en
dc.neeo.contributor McMorrow|Tara|aut| en
dc.description.othersponsorship Enterprise Ireland en
dc.description.admin au, sp, ab, li - TS 16.04.12 en


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