title: Role of p38 map kinase in glycine-induced hepatocyte resistance to hypoxic injury.
abstract: OBJECTIVE
  Glycine hepatoprotection is well known. However, the mechanisms involved are still poorly characterized.
  
  
  METHODS
  Glycine protection was investigated in isolated rat hepatocytes pretreated with 2 mmol/L glycine 15 min before incubation under hypoxic conditions.
  
  
  RESULTS
  Glycine significantly reduced Na+ overload and hepatocyte death caused by hypoxia. Glycine protection required the activation of a signal pathway involving Src, Pyk2 and p38 MAP kinases. Glycine treatment also induced a 11% increase of hepatocyte volume and transient ATP release. The prevention of cell swelling by hepatocyte incubation in a hypertonic medium as well as the degradation of extracellular ATP with apyrase or the block P2 purinergic receptors with suramin reverted glycine-induced cytoprotection and inhibited Src, Pyk2 and p38 MAPK activation. Glycine down-modulated Na+/H+ exchanger (NHE) activity, without affecting the development of intracellular acidosis during hypoxia. Such an effect was reverted by inhibiting p38 MAPK that also abolished glycine protection against Na+ overload caused by hypoxia.
  
  
  CONCLUSIONS
  Glycine-induced ATP release in response to a moderate hepatocyte swelling led to the autocrine stimulation of P2 receptors and to the activation of Src, Pyk2 and p38 MAPK that increased hepatocyte resistance to hypoxia by preventing Na+ influx through NHE.
authors.affiliation: Department of Medical Sciences, University A. Avogadro, Novara, Italy. carini@med.unipmn.it
authors.forename: Rita
authors.initials: R
authors.lastname: Carini
authors.forename: Elisa
authors.initials: E
authors.lastname: Alchera
authors.forename: Gianluca
authors.initials: G
authors.lastname: Baldanzi
authors.forename: Daniela
authors.initials: D
authors.lastname: Piranda
authors.forename: Roberta
authors.initials: R
authors.lastname: Splendore
authors.forename: Maria
authors.initials: M
authors.lastname: Grazia De Cesaris
authors.forename: Paolo
authors.initials: P
authors.lastname: Caraceni
authors.forename: Andrea
authors.initials: A
authors.lastname: Graziani
authors.forename: Emanuele
authors.initials: E
authors.lastname: Albano
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D019898:Autocrine Communication; D015687:Cell Hypoxia / Q000502:physiology*; D019610:Cytoprotection; D004789:Enzyme Activation; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism; D005998:Glycine / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D015398:Signal Transduction; D012964:Sodium / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D014867:Water / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D018048:Receptors, Purinergic P2; D017923:Sodium-Hydrogen Exchangers; D014867:Water; D000255:Adenosine Triphosphate; D012964:Sodium; D051418:Focal Adhesion Kinase 2; D019061:src-Family Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D005998:Glycine