Melatonin regulates L-Arginine transport and NADPH oxidase in young rats with bile duct ligation: Role of protein kinase C

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- (PKC-) 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- 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- 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.