title: L-carnitine protects against carboplatin-mediated renal injury: AMPK- and PPARα-dependent inactivation of NFAT3.
abstract: We have previously shown that carboplatin induces inflammation and apoptosis in renal tubular cells (RTCs) through the activation of the nuclear factor of activated T cells-3 (NFAT3) protein by reactive oxygen species (ROS), and that the ROS-mediated activation of NFAT3 is prevented by N-acetyl cysteine and heme oxygenase-1 treatment. In the current study, we investigated the underlying molecular mechanisms of the protective effect of L-carnitine on carboplatin-mediated renal injury. Balb/c mice and RTCs were used as model systems. Carboplatin-induced apoptosis in RTCs was examined using terminal-deoxynucleotidyl-transferase-mediated dUTP nick end labeling. We evaluated the effects of the overexpression of the peroxisome-proliferator-activated receptor alpha (PPARα) protein, the knockdown of PPARα gene, and the blockade of AMPK activation and PPARα to investigate the underlying mechanisms of the protective effect of L-carnitine on carboplatin-mediated renal injury. Carboplatin reduced the nuclear translocation, phosphorylation, and peroxisome proliferator responsive element transactivational activity of PPARα. These carboplatin-mediated effects were prevented by L-carnitine through a mechanism dependent on AMPK phosphorylation and subsequent PPARα activation. The activation of PPARα induced cyclooxygenase 2 (COX-2) and prostacyclin (PGI2) synthase expression that formed a positive feedback loop to further activate PPARα. The coimmunoprecipitation of the nuclear factor (NF) κB proteins increased following the induction of PPARα by L-carnitine, which reduced NFκB transactivational activity and cytokine expression. The in vivo study showed that the inactivation of AMPK suppressed the protective effect of L-carnitine in carboplatin-treated mice, indicating that AMPK phosphorylation is required for PPARα activation in the L-carnitine-mediated protection of RTC apoptosis caused by carboplatin. The results of our study provide molecular evidence that L-carnitine prevents carboplatin-mediated apoptosis through AMPK-mediated PPARα activation.
authors.affiliation: Department of Nephrology, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan.
authors.forename: Yuh-Mou
authors.initials: YM
authors.lastname: Sue
authors.affiliation: Department of Anatomy, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Hsiu-Chu
authors.initials: HC
authors.lastname: Chou
authors.affiliation: Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan; Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chih-Cheng
authors.initials: CC
authors.lastname: Chang
authors.affiliation: Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan; Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Nian-Jie
authors.initials: NJ
authors.lastname: Yang
authors.affiliation: Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan; Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chou
authors.affiliation: Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan; Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Shu-Hui
authors.initials: SH
authors.lastname: Juan
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics*; D058186:Acute Kidney Injury / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016190:Carboplatin / Q000009:adverse effects; D002331:Carnitine / Q000008:administration & dosage*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D007668:Kidney / Q000187:drug effects / Q000293:injuries / Q000473:pathology; D051379:Mice; D050778:NFATC Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D047493:PPAR alpha / Q000096:biosynthesis* / Q000235:genetics; D020011:Protective Agents / Q000008:administration & dosage; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D050778:NFATC Transcription Factors; C494010:NFATC4 protein, human; D047493:PPAR alpha; D020011:Protective Agents; D017382:Reactive Oxygen Species; D016190:Carboplatin; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D055372:AMP-Activated Protein Kinases; D002331:Carnitine
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