Role of p38 map kinase in glycine-induced hepatocyte resistance to hypoxic injury

Background/Aims: 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.