| Summary: | 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. === Pharmaceutical Sciences, Faculty of === Graduate
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