Negative regulation of diacylglycerol kinase θ mediates adenosine-dependent hepatocyte preconditioning

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RESEARCH PRODUCT

Negative regulation of diacylglycerol kinase θ mediates adenosine-dependent hepatocyte preconditioning

Emanuele Albano Mariapaola Nitti Andrea Graziani W J Van Blitterswijk M. Gaggianesi C. Imarisio R. Carini Gianluca Baldanzi C. Dal Ponte E. Alchera Cinzia Domenicotti

subject

Male Diacylglycerol Kinase medicine.medical_specialty Adenosine Receptor Adenosine A2A p38 mitogen-activated protein kinases Biology Quinazolinone chemistry.chemical_compound Piperidine cytoprotection Piperidines Downregulation and upregulation Diacylglycerol kinase theta Internal medicine medicine Enzyme Inhibitor hepatocytes adenosine RhoA hypoxia cytoprotection Animals Hepatocyte Enzyme Inhibitors Rats Wistar Molecular Biology Cells Cultured Protein kinase C Quinazolinones Diacylglycerol kinase Cell Death Animal hypoxia Kinase Receptors Purinergic P1 RhoA Cell Biology Phosphatidic acid Adenosine Cell Hypoxia Rats Cell biology Endocrinology chemistry Hepatocytes Rat rhoA GTP-Binding Protein medicine.drug

description

In liver ischemic preconditioning (IP), stimulation of adenosine A2a receptors (A2aR) prevents ischemia/reperfusion injury by promoting diacylglycerol-mediated activation of protein kinase C (PKC). By concerting diacylglycerol to phosphatidic acid, diacylglycerol kinases (DGKs) act as terminator of diacylglycerol signalling. This study investigates the role of DGK in the development of hepatocyte IP. DGK activity and cell viability were evaluated in isolated rat hepatocytes preconditioned by 10 min hypoxia followed by 10 min re-oxygenation or by the treatment with the A2aR agonist, CGS21680, and subsequently exposed to prolonged hypoxia. We observed that after IP or A2aR activation, a decrease in DGK activity was associated with the onset of hepatocyte tolerance to hypoxia. CGS21680-induced stimulation of A2aR specifically inhibited DGK isoform θ by activating RhoA-GTPase. Consistently, both siRNA-mediated downregulation of DGK θ and hepatocyte pretreatment with the DGK inhibitor R59949 induced cell tolerance to hypoxia. The pharmacological inhibition of DGK was associated with the diacylglycerol-dependent activation of PKC δ and ε and of their downstream target p38 MAPK. In conclusion, we unveil a novel signalling pathway contributing to the onset of hepatocyte preconditioning, which through RhoA-GTPase, couples A2aR to the downregulation of DGK. Such an inhibition is essential for the sustained accumulation of diacylglycerol required for triggering PKC-mediated survival signals. © 2010 Macmillan Publishers Limited All rights reserved.

year	journal	country	edition	language
2010-01-01	Cell Death & Differentiation

https://doi.org/10.1038/cdd.2009.210