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    Evaluations of a human kidney (HK2 cells) model for drug-induced cytotoxicity and BK virus infection

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    Author
    Kinjo, Minori
    Advisor
    Dowling, Thomas C.
    Date
    2008
    Type
    dissertation
    
    Metadata
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    Abstract
    Renal transplant patients receive drugs such as tacrolimus (TAC), sirolimus (SRL), cyclosporin (CSA) for immunosuppression, and low-dose cidofovir (CID) for treatment of BK virus associated nephropathy (BKVN). In this series of studies, we evaluated the effects of clinically achievable concentrations of drug combination therapy on p-glycoprotein (P-GP) and organic anion (OA) transporters (OAT-1,-3 and MRP2) expression and function in human renal proximal tubule (HK2) cells. HK2 cells were further evaluated as a host for BK virus and a model for drug screening for the treatment of BKVN. HK2 cells were exposed to drug combinations over 5 days with determination of P-GP and OAT-1 expressions and functions in HK2 cells. P-GP function was assessed by rhodamine 123 (R123) uptake and OA transport activity was evaluated by para-aminohippurate transport (PAH) during acute and chronic exposures. Exposure to supraclinical concentrations of TAC, SRL and CSA resulted in significant reductions in cell viability whereas expression of P-GP, and OA transporters remained unchanged. A significant concentration-dependent toxicity was demonstrated by trypan blue exclusion but not by XTT assay, suggesting the importance of drug-uptake mechanism in designing experiments. R123 accumulation was significantly increased during TAC, SRL and CSA exposure. PAH transport remained unchanged in the presence of TAC, SRL, and CSA; however a trend towards decreased transport in the presence of CID was observed. HK2 cells were shown to express Caveolin-1, and were permeable to BK virus. Viral growth was gradual after 20 days post-infection, and stabilized after 55 days. A possible dormant stage of BK viral cycle was observed. The efficacy of CID was tested on the BK virus-infected HK2 cell model, and the quantitative PCR data showed that 24-hour CID exposure suppressed viral replications after 4 days incubation in a concentration-dependent manner. The key finding in these studies suggest that immunosuppressants used in renal patients may impair renal P-GP function. Exposure to drug combinations including CID may increase the risk of nephrotoxicity in patients receiving immunosuppressants. A BK virus infected HK2 cell model was developed that could be further utilized to study BK virus infection and new treatments for BKVN.
    Description
    University of Maryland, Baltimore. Pharmaceutical Sciences. Ph.D. 2008
    Keyword
    Health Sciences, Pharmacology
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/969
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    Theses and Dissertations All Schools
    Theses and Dissertations School of Pharmacy

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