Peroxisome proliferator-activated receptor alpha plays a crucial role in l-carnitine anti-apoptosis effect in renal tubular cells

Background. l-carnitine is synthesized mainly in the liver and kidneys from lysine and methionine from dietary sources. Many reports have shown that l-carnitine can protect certain cells against the toxicity of several anticancer and toxic agents, although the detailed mechanism is poorly understood. In this study, we investigated the protective effect of l-carnitine and its molecular mechanism in renal tubular cells undergoing gentamicin-induced apoptosis.Methods. Rat tubular cell line (NRK-52E) and mice were used as the model system. Gentamicin-induced apoptosis in renal tubular cells was examined using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labelling. We introduced short interfering RNA transfection and gene-deficient mice to investigate the protective mechanism of l-carnitine.Results. We found that l-carnitine inhibited gentamicin-induced reactive oxygen species generation and correlative apoptotic pathways, resulting in the protection of NRK-52E cells from gentamicin-induced apoptosis. The treatment of l-carnitine also lessened gentamicin-induced renal tubular cell apoptosis in mice. l-carnitine was found to increase the prostacyclin (PGI2) generation in NRK-52E cells. The siRNA transfection for PGI2 synthase significantly reduced l-carnitine-induced PGI2 and l-carnitine's protective effect. We found that the activity of the potential PGI2 nuclear receptor, peroxisome proliferator-activated receptor alpha (PPARα), was elevated by l-carnitine treatment. The siRNA-mediated blockage of PPARα considerably reduced the anti-apoptotic effect of l-carnitine. In PPARα-deficient mice, l-carnitine treatment also lost the inhibitory effect on gentamicin-induced apoptosis in kidneys.Conclusions. Based on these findings, we suggest that l-carnitine protects renal tubular cells from gentamicin-induced apoptosis through PGI2-mediated PPARα activation.