Purinergic P2Y2 receptors promote hepatocyte resistance to hypoxia.

Abstract

BACKGROUND/AIMS:

ATP stimulation of purinergic P2 receptors (P2YR and P2XR) regulates several hepatic functions. Here we report the involvement of ATP-mediated signals in enhancing hepatocyte tolerance to lethal stress.

METHODS:

The protection given by purinergic agonists was investigated in rat hepatocytes exposed to hypoxia.

RESULTS:

ATP released after hypotonic stress (200 mOsm/L) as well as P2YR agonists prevented hepatocyte killing by hypoxia with efficiency ranking UTP > ATPgammaS > ADPbetaS, whereas the P2XR agonist, methylene-adenosine-5'-triphosphate, was ineffective. Adenosine-5'-O-3-thiotriphosphate (ATPgammaS; 100 micromol/L) also prevented Na+ -overload in hypoxic cells by inhibiting the Na+/H+ exchanger, without interfering with hypoxic acidosis. ATPgammaS activated Src and promoted a Src-dependent stimulation of both ERK1/2 and p38MAPK. Blocking p38MAPK with SB203580 reverted the protection given by ATPgammaS on both cell viability and Na+ accumulation, whereas ERK1/2 inhibition with PD98058 was ineffective. An increased phosphorylation of ERK1/2 was also evident in untreated hypoxic hepatocytes. PD98058 ameliorated Na+ accumulation and cell death caused by hypoxia. Hepatocyte pre-treatment with ATPgammaS reverted ERK1/2 activation in hypoxic cells. SB203580 blocked the effects of ATPgammaS on both ERK1/2 and Na+/H+ exchanger.

CONCLUSIONS:

The activation of p38MAPK by P2Y2R increases hepatocyte resistance to hypoxia by down-modulating ERK1/2-mediated signals that promote Na+ influx through the Na+/H+ exchanger.

• Authors: Rita Carini, Elisa Alchera, Maria Grazia De Cesaris, Roberta Splendore, Daniela Piranda, Gianluca Baldanzi, Emanuele Albano
• Journal: Journal of hepatology (J Hepatol) Vol. 45 Issue 2 Pg. 236-45 (Aug 2006) ISSN: 0168-8278 [Print] Netherlands
• PMID: 16644060 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Affinity Labels
• Organic Chemicals
• P2ry2 protein, rat
• PD 98058
• Receptors, Purinergic P2
• Receptors, Purinergic P2Y2
• adenosine 5'-O-(3-thiotriphosphate)
• Adenosine Triphosphate
• Sodium

Topics

• Adenosine Triphosphate (analogs & derivatives, pharmacology)
• Affinity Labels (pharmacology)
• Animals
• Cell Death (drug effects)
• Disease Models, Animal
• Hepatocytes (metabolism, pathology)
• Hypoxia (drug therapy, metabolism, pathology)
• Male
• Organic Chemicals (pharmacology)
• Rats
• Rats, Wistar
• Receptors, Purinergic P2 (drug effects, metabolism)
• Receptors, Purinergic P2Y2
• Reperfusion Injury (drug therapy, metabolism, pathology)
• Signal Transduction (drug effects)
• Sodium (metabolism)