The Development of a Cellular model of Nephrosis to Evaluate Nephrotoxic Biomarkers

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dc.contributor.advisor Bashir, R en Marlow, Gareth en 2012-04-01T22:52:52Z en 2012-07-04T00:38:04Z en 2006 en
dc.identifier.citation Sub type: PhD Thesis. Supervisors: Bashir R. The University of Durham, 2006 en
dc.identifier.uri en
dc.description.abstract Nephrotoxicity is one of the major causes for compound failure late in the drug development process. Pharmaceutical companies are interested in identifying biomarkers of nephrotoxicity which can be used to identify potential toxic compounds earlier in the development process and hence reduce the overall time and costs involved in bringing a drug to market. I developed a cellular model of nephrosis, in NRK cells, using the well characterized nephrotoxicant compound puromycin aminonuceloside (PAN). Using this cellular model I examined the expression of kidney specific genes. Two podocyte specific proteins, podoplanin and podocalyxin were found to be specifically down-regulated. Podoplanin showed an almost universal 65% reduction in the level of gene expression after PAN treatment. Podocalyxin showed a dose-dependent reduction in expression, which reached a peak of 85% reduced expression at the highest PAN dose tested. A cell aggregation assay was developed to quantify the effect of PAN induced nephrosis on the cell adhesion properties of the NRK cells. It was found that PAN nephrosis had a significant effect on the cells ability to aggregate and to remain adhesive. However cells which lost the ability to adhere were still found to be viable. Integrin a3 protein expression was found not be altered in response to PAN treatment as determined by immunofluorescence microscopy however Laminin β2 was found to form aggregates in response to PAN treatment. The actin cytoskeleton was also found to be severely disrupted as a result of PAN induced nephrosis. Based on these studies podocalyxin has been identified as a potential genetic biomarker of nephrosis, however further study of podocalyxin expression in other models of nephrosis is required before podocalyxin can be routinely used as a predictor of nephrotoxicity. en
dc.description.uri en
dc.publisher Durham E-Theses en
dc.relation.ispartof PhD Thesis - University of Auckland en
dc.relation.replaces en
dc.relation.replaces 2292/16295 en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. en
dc.rights.uri en
dc.title The Development of a Cellular model of Nephrosis to Evaluate Nephrotoxic Biomarkers en
dc.type Thesis en Biological Sciences en Durham University en Doctoral en PhD en
dc.rights.holder Copyright: The author en en
dc.rights.accessrights en
pubs.elements-id 244120 en
pubs.record-created-at-source-date 2011-11-24 en

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