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.

Original languageEnglish
Article numbere104079
JournalPLoS One
Volume9
Issue number8
DOIs
Publication statusPublished - Aug 4 2014

Fingerprint

NFATC Transcription Factors
PPAR alpha
AMP-Activated Protein Kinases
Carnitine
carnitine
Carboplatin
inactivation
T-lymphocytes
kidneys
Kidney
Wounds and Injuries
Chemical activation
kidney cells
Phosphorylation
apoptosis
Apoptosis
protective effect
phosphorylation
heme oxygenase (biliverdin-producing)
reactive oxygen species

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

L-carnitine protects against carboplatin-mediated renal injury : AMPK- And PPARα-dependent inactivation of NFAT3. / Sue, Yuh Mou; Chou, Hsiu Chu; Chang, Chih-Cheng; Yang, Nian Jie; Chou, Ying; Juan, Shu Hui.

In: PLoS One, Vol. 9, No. 8, e104079, 04.08.2014.

Research output: Contribution to journalArticle

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AU - Sue, Yuh Mou

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AU - Chang, Chih-Cheng

AU - Yang, Nian Jie

AU - Chou, Ying

AU - Juan, Shu Hui

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