title: Melatonin regulates L-arginine transport and NADPH oxidase in young rats with bile duct ligation: role of protein kinase C.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: You-Lin
authors.initials: YL
authors.lastname: Tain
authors.forename: Chih-Cheng
authors.initials: CC
authors.lastname: Chen
authors.forename: Chien-Te
authors.initials: CT
authors.lastname: Lee
authors.forename: Ying-Hsien
authors.initials: YH
authors.lastname: Kao
authors.forename: Jiunn-Ming
authors.initials: JM
authors.lastname: Sheen
authors.forename: Hong-Ren
authors.initials: HR
authors.lastname: Yu
authors.forename: Li-Tung
authors.initials: LT
authors.lastname: Huang
mesh_terms: D000818:Animals; D001119:Arginase / Q000378:metabolism; D001120:Arginine / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism*; D001692:Biological Transport; D027201:Cationic Amino Acid Transporter 1 / Q000378:metabolism; D001651:Cholestasis, Extrahepatic / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology; D003135:Common Bile Duct / Q000601:surgery*; D004195:Disease Models, Animal; D005260:Female; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology; D008026:Ligation; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008550:Melatonin / Q000008:administration & dosage / Q000494:pharmacology*; D019255:NADPH Oxidases / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D027201:Cationic Amino Acid Transporter 1; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; C018524:N,N-dimethylarginine; D001120:Arginine; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; C113162:Arg2 protein, rat; D001119:Arginase; D008550:Melatonin