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Characterisation of tools for studying renal mineral ion homeostasis and drug-induced nephrotoxicity

Wadey, Rebecca 2014. Characterisation of tools for studying renal mineral ion homeostasis and drug-induced nephrotoxicity. PhD Thesis, Cardiff University.
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Abstract

The complex interplay between regulatory factors of kidney mineral ion homeostasis are difficult to investigate in vivo. In addition, preclinical drug safety testing is limited by lack of translational tools for screening novel drugs for nephrotoxicity. At Cardiff University, my PhD project aimed to characterise tools to address these needs. At AstraZeneca, the use of tissue biomarkers as tools for assessing kidney injury in retrospective studies where urine biomarker samples are not available, was evaluated. To enable studies of mineral ion homeostasis, an in vitro human primary renal cell model was characterised. Cells expressed phenotypic marker proteins (E-, N-Cadherin) as well as proteins involved in mineral ion homeostasis (FGFR1-4, Klotho, NaPi IIa, NCX1, PMCA1). They also exhibited morphological features and functional characteristics of renal cells in vivo. Data were presented as an oral abstract communication at the American Society of Nephology Meeting, 2013. To enable studies of drug-induced nephrotoxicity, in vitro primary mouse and human renal cell models were characterised. A concentration-dependent increase in apoptosis was observed in mouse cells following 24-hour treatment with medium containing cisplatin, cyclosporin A and BEA. Following 24-hour treatment, the same nephrotoxins increased expression of the kidney injury biomarkers kidney injury molecule-1 (KIM-1) and osteopontin. Human cells responded to 24-hour treatment with medium containing cisplatin with expression of KIM-1, osteopontin and clusterin. Parallel use of such rodent and human models would revolutionise preclinical translational drug safety assessment. Cisplatin-treated rats were used to evaluate the use of tissue biomarkers as tools in studies where urine biomarker samples are not available, such as retrospective studies in drug safety testing. Of the biomarkers investigated, KIM-1 and osteopontin showed greatest correlation with their corresponding urinary biomarkers. As such, they offer greatest utility as tissue biomarkers in retrospective studies. Data were published in Toxicologic Pathology (Wadey et al. 2013).

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Biosciences
Subjects: Q Science > QP Physiology
Funders: BBSRC, AstraZeneca
Date of First Compliant Deposit: 30 March 2016
Last Modified: 19 Mar 2016 23:54
URI: http://orca-mwe.cf.ac.uk/id/eprint/71398

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