Abstract
Background:
Bile duct ligation (BDL) is a commonly used cholestatic liver disease (CLD) model. We recently found that L-arginine levels were significantly raised by melatonin in young rats with BDL. We hypothesized that protein kinase C-α (PKC-α) is involved in the increases of L-arginine in melatonin-treated BDL rats. In addition, we tested whether melatonin prevents nicotinamide adenine dinucleotide phosphate (NADPH) oxidase–induced reactive oxygen species (ROS) production, in rats with BDL, through PKC.
Methods:
Four groups of young male rats were studied: shams (n = 6), untreated BDL rats (n = 9), melatonin-treated shams (n = 6, M), and melatonin-treated BDL rats (n = 6, BDL + M). Melatonin-treated rats received daily melatonin 1 mg/kg/d via i.p. injection. All surviving rats were killed 14 d after surgery.
Results:
Melatonin prevented BDL-induced mortality and kidney injury. Melatonin additionally increased L-arginine concentrations in BDL liver, which is correlated with decreased PKC-α translocation. Next, melatonin increased L-arginine levels in BDL kidneys, which was correlated with decreased renal levels of arginase II. In the BDL kidney, melatonin decreased PKC-β translocation, reduced p47phox translocation, and diminished NADPH-dependent superoxide production.
Conclusion:
Melatonin inhibits PKC-α to increase cationic amino acid transporter-1 (CAT-1)–mediated L-arginine uptake in BDL liver, whereas it inhibits PKC-β to reduce NADPH-dependent superoxide production.
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Acknowledgements
We thank Samuel H.H. Chan and the Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, for providing space to support electron paramagnetic resonance.
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Tain, YL., Chen, CC., Lee, CT. et al. Melatonin regulates L-arginine transport and NADPH oxidase in young rats with bile duct ligation: role of protein kinase C. Pediatr Res 73, 395–401 (2013). https://doi.org/10.1038/pr.2012.203
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DOI: https://doi.org/10.1038/pr.2012.203
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