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.
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.