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Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York 10032
We have recently demonstrated protection against renal ischemic-reperfusion injury in vivo by A1- and A2a-adenosine receptor (AR) modulations. To further elucidate the signaling cascades of AR-induced cytoprotection against reperfusion/oxidant-mediated injury, immortalized human proximal tubule (HK-2) cells were treated with H2O2. H2O2 caused dose- and time-dependent HK-2 cell death that was measured by lactate dehydrogenase release and trypan blue dye uptake. Adenosine protected against H2O2-induced HK-2 cell death by means of A1- and A2a-AR activation. A1-AR-mediated protection involves pertussis toxin-sensitive G proteins and protein kinase C, whereas A2a-AR-mediated protection involves protein kinase A activation by means of cAMP and activation of the cAMP response element binding protein. Moreover, protein kinase A activators (forskolin and Sp-isomer cAMP) also protected HK-2 cells against H2O2 injury. De novo gene transcription and protein synthesis are required for both A1- and A2a-AR-mediated cytoprotection as actinomycin D and cycloheximide, respectively, blocked cytoprotection. Chronic treatments with a nonselective AR agonist abolished the protection by adenosine. Moreover, chronic treatments with a nonselective AR antagonist increased the endogenous tolerance of HK-2 cells against H2O2. We concluded that A1- and A2a-AR activation protects HK-2 cells against H2O2-induced injury by means of distinct signaling pathways that require new gene transcription and new protein synthesis.
adenosine 3',5'-cyclic monophosphate; immortalized human proximal tubule cells; hydrogen peroxide; pertussis toxin-sensitive G proteins; protein kinase A; protein kinase C
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