Effects of serum lipoproteins on cyclosporine A cellular uptake and renal toxicity in vitro

In-vitro studies were performed to shed light on previous findings that showed increased uptake of cyclosporine A in the kidneys and liver of hyperlipidemic rats, and increased signs of kidney toxicity. Hepatocytes were obtained from rats, cultured, and exposed to a diluted serum from hyperlipidemic rats. Some cells were also exposed to lipid-lowering drugs. After washing out the rat serum or lipid-lowering drugs, cells were exposed to cyclosporine A embedded in serum lipoproteins. Pretreatment with hyperlipidemic serum and lipid-lowering drugs was associated with an increased uptake of cyclosporine A. As expected, atorvastatin caused an increase in low density lipoprotein receptor and a decrease in MDR1A mRNA in the hepatocytes. A decrease in NRK-52E rat renal tubular cellular viability caused by cyclosporine A was noted when cells were preincubated with diluted hyperlipidemic serum. This was matched with evidence of hyperlipidemic-serum-associated increases in the NRK-52E cellular uptake of cyclosporine A and rhodamine-123. The findings of these experiments suggested that in hyperlipidemia the expression and (or) the functional activity of P-glycoprotein was diminished, leading to greater hepatic and renal uptake of cyclosporine A, and renal cellular toxicity. Key words: hepatocytes, hyperlipidemia, lipoprotein receptors, NRK-52E cells, P-glycoprotein. Des etudes in vitro ont ete realisees afin de faire la lumiere sur des resultats obtenus precedemment, qui ont revele une captation accrue de cyclosporine A dans les reins et le foie de rats hyperlipidemiques ainsi que des signes accrus de toxicite renale. Des hepatocytes de rats ont ete isoles, cultives et exposes a du serum de rat hyperlipidemique dilue. Certaines cellules ont aussi ete exposees a des hypolipidemiants. Apres avoir rince les cellules du serum de rat ou des hypolipidemiants, elles ont ete exposees a la cyclosporine A enrobee dans des lipoproteines seriques. Le pretraitement au serum hyperlipidemique et aux hypolipidemiants etait associe a une captation accrue de cyclosporine A. Comme attendu, l'atorvastatine induisait une augmentation de l'expression du recepteur des lipoproteines de faible densite ainsi qu'une diminution de l'expression de l'ARNm de MDR1A dans les hepatocytes. Une diminution la viabilite des cellules de tubules renaux de rats NRK-52E induite par la cyclosporine A a ete notee lorsque les cellules etaient preincubees avec le serum hyperlipidemique dilue. Cela coincidait avec l'augmentation de la captation de cyclosporine A et de rhodamine-123 associee au serum hyperlipidemique dans les cellules NRK-52E. Les resultats de ces experiences suggerent qu'en situation d'hyperlipidemie, l'expression et (ou) l'activite fonctionnelle de la P-glycoproteine etait diminuee, conduisant a une captation accrue de clyclosporine A par le foie et les reins, ainsi qu'a une toxicite cellulaire renale. [Traduit par la Redaction] Mots-cles: hepatocytes, hyperlipidemie, recepteurs de lipoproteines, cellules NRK-52E, P-glycoproteine.
Introduction In rats, experimental hyperlipidemia (HL) is associated with increased concentrations of the immunosuppressive agent, cyclosporine A (CyA) in the kidneys and liver (Aliabadi et al. 2006). This finding has [...]