Role of p38 map kinase in glycine-induced hepatocyte resistance to hypoxic injury.
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.
Carini
Rita
R
Department of Medical Sciences, University A. Avogadro, Novara, Italy. carini@med.unipmn.it
Alchera
Elisa
E
Baldanzi
Gianluca
G
Piranda
Daniela
D
Splendore
Roberta
R
Grazia De Cesaris
Maria
M
Caraceni
Paolo
P
Graziani
Andrea
A
Albano
Emanuele
E
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
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