Preconditioning and adenosine protect human proximal tubule cells in an in vitro model of ischemic injury.
Renal ischemic reperfusion injury results in unacceptably high mortality and morbidity during the perioperative period. It has been recently demonstrated that ischemic preconditioning or adenosine receptor modulations attenuate renal ischemic reperfusion injury in vivo. An in vitro model of ischemic renal injury was used in cultured human proximal tubule (HK-2) cells to further elucidate the protective signaling cascades against renal ischemic reperfusion injury. ATP depletion preconditioning (1 h of antimycin A and 2-deoxyglucose treatment followed by 1 h of recovery), adenosine, an A(1) adenosine receptor selective agonist, or an A(2a) adenosine receptor selective agonist significantly attenuated subsequent severe ATP depletion injury of HK-2 cells. In contrast, an adenosine receptor antagonist failed to prevent protection induced by ATP depletion preconditioning. Cytoprotection by ATP depletion preconditioning or A(1) adenosine receptor activation was prevented by inhibitors of extracellular signal-regulated mitogen-activated kinases, protein kinase C, and tyrosine kinases. The A(1) and A(2a) adenosine receptor-mediated cytoprotection were also dependent on G(i/o) proteins and PKA activation, respectively. It is concluded that ATP depletion preconditioning and A(1) and A(2a) adenosine receptor activation protect HK-2 cells against severe ATP depletion injury via distinct signaling pathways.
Lee
H Thomas
HT
Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA. tl128@columbia.edu
Emala
Charles W
CW
D000241:Adenosine / Q000494:pharmacology*; D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors; D000968:Antimycin A / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D016923:Cell Death; D002461:Cell Line, Transformed; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D019610:Cytoprotection; D003847:Deoxyglucose / Q000494:pharmacology; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D007476:Ionophores / Q000494:pharmacology; D007511:Ischemia / Q000473:pathology* / Q000503:physiopathology*; D019194:Ischemic Preconditioning; D007687:Kidney Tubules, Proximal / Q000098:blood supply* / Q000473:pathology / Q000503:physiopathology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D015398:Signal Transduction
D007476:Ionophores; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1; D000001:Calcimycin; D000968:Antimycin A; D000255:Adenosine Triphosphate; D003847:Deoxyglucose; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D000241:Adenosine