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The effects of lipoproteins on cyclosporine A toxicity and uptake in renal cells

University of British Columbia

Cyclosporine A (CSA) is an effective immunosuppressant, but side effects such as renal toxicity can limit its therapeutic use. The hydrophobicity of CSA results in significant association of the drug with lipoproteins in the blood. Lipid levels in patients undergoing CSA therapy are correlated with CSA-induced renal toxicity. Renal damage in the glomerulus, the site of blood filtration, results in increased lipoprotein leakage into the proximal tubule, a major site of CSA toxicity. The current studies investigate the effects of lipoproteins on CSA-induced renal toxicity in the pig epithelial cell line LLC-PK1. Toxicity and uptake of CSA in the LLC-PK1 cell line were measured by protein synthesis and tritiated CSA, respectively. The three main classes of lipoproteins, very low (VLDL), low (LDL) and high density lipoproteins (HDL) at hypo-, normo- and hyperlipidemic levels were tested for their ability to affect CSA-induced toxicity and uptake. The major component of each lipoprotein was also tested to determine its effects on CSA-induced toxicity and uptake. The involvement of lipoprotein receptors as determinants in mediating toxicity was also examined. ApoA-I, the major protein component of HDL, and intact LDL particles showed the most significant effects on CSA uptake and toxicity. The uptake and toxicity of CSA was effectively reduced with elevated LDL concentrations but showed a significant increase (p<0.05) when incubated with elevated concentrations of apoA-I. Increasing VLDL and HDL concentrations slightly reduced CSA toxicity and uptake, but showed little effect with increased incubation time. Triglyceride and cholesterol, the respective major components of VLDL and LDL did not alter CSA uptake or toxicity under the conditions tested. LDL and apoA-I are identified as the major effectors of CSA toxicity and uptake in LLC-PK1 cells. These effects may be mediated through receptors such as the LDL receptor or those involved in protein re-absorption. The data presented here clearly demonstrate a relationship between CSA-induced toxicity and the nature of the associated lipoprotein. Careful monitoring of lipid levels in patients undergoing CSA therapy may improve patient care and minimize CSA-induced toxicity in the kidney.

Thesis/Dissertation

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2009-07-13

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http://hdl.handle.net/2429/10725

Pharmaceutical Sciences

University of British Columbia

UBCV

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