Effects of lipoproteins on cyclosporine A toxicity and uptake in LLC-PK1 pig kidney cells

Cyclosporine A (CSA) is an effective immunosuppressant, but side effects su ch as renal toxicity can limit its therapeutic use. The current studies inv estigate the effects of lipoproteins on CSA-induced renal toxicity in the p ig epithelial cell line LLC-PK1. Protein synthesis and tritiated CSA were u sed as measures of toxicity and uptake of CSA, respectively, in the LLC-PK1 . cell line. The three main classes of lipoproteins, very low (VLDL), low ( LDL), and high density lipoproteins (HDL) at hypo-, normo-, and hyperlipide mic levels were tested for their ability to affect CSA-induced toxicity and uptake. The major component of each lipoprotein was also tested to determi ne its effects on CSA-induced toxicity and uptake. ApoA-I, the major protei n component of HDL, and intact LDL particles showed the most significant ef fects of CSA uptake and toxicity. The uptake and toxicity of CSA was effect ively reduced with elevated LDL concentrations but showed a significant inc rease (p < 0.05) when incubated with elevated concentrations of apoA-I. Inc reasing VLDL and HDL concentrations slightly reduced CSA toxicity and uptak e, but showed little effect with increased incubation time. Triglyceride an d cholesterol, the respective major components of VLDL and LDL, did not alt er CSA uptake or toxicity under the conditions tested. LDL and apoA-I are i dentified as the major effectors of CSA toxicity and uptake in LLC-PK1 cell s. These effects may be mediated through receptors such as the LDL receptor or those involved in protein reabsorption. The data presented here clearly demonstrate a relationship between CSA-induced toxicity and the nature of the associated lipoprotein. (C) 2001 Wiley-Liss, Inc. and the American Phar maceutical Association.