Acute and delayed renal protection against renal ischemia and reperfusion injury with A1 adenosine receptors.
We showed previously that activation of A(1) adenosine receptors (AR) protects against renal ischemia-reperfusion (IR) injury in rats and mice. In the heart, transient A(1)AR activation produces biphasic protective effects: acute protection wanes after several hours but protective effects return 24-72 h later (second window of protection). In this study, we determined whether A(1)AR activation produces delayed renal protection and elucidated the mechanisms of acute and delayed renal protection. A(1)AR wild-type mice were subjected to 30-min renal ischemia and 24 h of reperfusion to produce acute renal failure. Pretreatment with a selective A(1)AR agonist 2-chloro-N(6)-cyclopentyladenosine (CCPA; 0.1 mg/kg bolus ip) either 15 min or 24 h before renal ischemia protected against renal IR injury and reduced renal corticomedullary necrosis, apoptosis, and inflammation. Transient A(1)AR activation led to phosphorylation of extracellular signal-regulated protein kinase mitogen-activated protein kinase (ERK MAPK), Akt, and heat shock protein 27 (HSP27). Moreover, induction of HSP27 and Akt occurred with CCPA treatment. Inhibition of PKC with chelerythrine prevented acute but not delayed renal protection with A(1)AR activation. Moreover, deletion of PI3Kgamma or inhibition of Akt, but not inhibition of ERK, prevented delayed and acute renal protection with A(1)AR activation. Inhibition of G(i/o) with pertussis toxin obliterated both acute and delayed A(1)AR-mediated renal protection. In contrast to renal protection with delayed ischemic preconditioning, nitric oxide synthase activity was not induced with delayed A(1)AR-mediated renal protection. Therefore, transient activation of renal A(1)AR led to acute as well as delayed protective effects against renal IR injury via distinct signaling pathways.
Joo
Jin Deok
JD
Dept. of Anesthesiology, Anesthesiology Research Laboratories, Columbia Univ., P&S Box 46 (PH-5 630 West 168th St., New York, NY 10032-3784, USA.
Kim
Mihwa
M
Horst
Patrick
P
Kim
Jeehee
J
D'Agati
Vivette D
VD
Emala
Charles W
CW
Lee
H Thomas
HT
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western; D003404:Creatinine / Q000097:blood; D053938:DNA Fragmentation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D006360:Heat-Shock Proteins / Q000235:genetics / Q000502:physiology; D007150:Immunohistochemistry; D007672:Kidney Cortex / Q000201:enzymology / Q000502:physiology; D007674:Kidney Diseases / Q000517:prevention & control*; D007677:Kidney Function Tests; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D009336:Necrosis; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000502:physiology; D011493:Protein Kinase C / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D043682:Receptor, Adenosine A1 / Q000235:genetics / Q000502:physiology*; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D006360:Heat-Shock Proteins; D043682:Receptor, Adenosine A1; D003404:Creatinine; D052247:Nitric Oxide Synthase Type II; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases