title: Peroxisome proliferator-activated receptor alpha plays a crucial role in L-carnitine anti-apoptosis effect in renal tubular cells.
abstract: 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 (PGI(2)) generation in NRK-52E cells. The siRNA transfection for PGI(2) synthase significantly reduced L-carnitine-induced PGI(2) and L-carnitine's protective effect. We found that the activity of the potential PGI(2) nuclear receptor, peroxisome proliferator-activated receptor alpha (PPARalpha), was elevated by L-carnitine treatment. The siRNA-mediated blockage of PPARalpha considerably reduced the anti-apoptotic effect of L-carnitine. In PPARalpha-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 PGI(2)-mediated PPARalpha activation.
authors.affiliation: Department of Internal Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Hsi-Hsien
authors.initials: HH
authors.lastname: Chen
authors.forename: Yuh-Mou
authors.initials: YM
authors.lastname: Sue
authors.forename: Cheng-Hsien
authors.initials: CH
authors.lastname: Chen
authors.forename: Yung-Ho
authors.initials: YH
authors.lastname: Hsu
authors.forename: Chun-Cheng
authors.initials: CC
authors.lastname: Hou
authors.forename: Chung-Yi
authors.initials: CY
authors.lastname: Cheng
authors.forename: Shih-Li
authors.initials: SL
authors.lastname: Lin
authors.forename: Wei-Lun
authors.initials: WL
authors.lastname: Tsai
authors.forename: Tzen-Wen
authors.initials: TW
authors.lastname: Chen
authors.forename: Tso-Hsiao
authors.initials: TH
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002331:Carnitine / Q000494:pharmacology / Q000502:physiology*; D002478:Cells, Cultured; D011464:Epoprostenol / Q000096:biosynthesis; D005839:Gentamicins / Q000008:administration & dosage; D007674:Kidney Diseases / Q000139:chemically induced / Q000517:prevention & control; D007684:Kidney Tubules / Q000166:cytology*; D051379:Mice; D047493:PPAR alpha / Q000502:physiology*; D051381:Rats
chemical_list: D005839:Gentamicins; D047493:PPAR alpha; D011464:Epoprostenol; D002331:Carnitine