Submitted on July 18, 2007
Accepted on October 9, 2007
Acute and delayed renal protection against renal ischemia and reperfusion injury with A1 adenosine receptors
Jin Deok Joo1, Mihwa Kim1, Patrick Horst2, Jeehee Kim1, Vivette D. D'Agati3, Charles W. Emala, Sr4, and H. Thomas Lee1*
1 Anesthesiology, Columbia University, New York, New York, United States
2 Anesthesiology, Columbia University, United States; Anesthesiology, Columbia University, New York, New York, United States
3 United States; Pathology, Columbia University, New York, New York, United States
4 Pathology, Columbia University, New York, New York, United States; Anesthesiology, Columbia University, New York, New York, United States
* To whom correspondence should be addressed. E-mail: tl128{at}columbia.edu.
We showed previously that activation of A1 adenosine receptors (AR) protects against renal ischemia reperfusion (IR) injury. In the heart, transient A1AR activation produces biphasic protective effects: acute protection wanes after several hours but protective effects return 24-72 hours later (second window of protection). In this study, we determined whether A1AR activation produces delayed renal protection and elucidated the mechanisms of acute and delayed renal protection. A1AR wild type (WT) mice were subjected to 30 min. renal ischemia and 24 hours of reperfusion to produce acute renal failure. Pretreatment with a selective A1AR agonist 2-chloro-N6-cyclopentyladenosine (CCPA, 0.1 mg/kg bolus i.p.) either 15 min. or 24 hr prior to renal ischemia protected against renal IR injury and reduced renal corticomedullary necrosis, apoptosis and inflammation. Transient A1AR 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 A1AR activation. Moreover, deletion of PI3K
or inhibition of Akt, but not inhibition of ERK, prevented delayed and acute renal protection with A1AR activation. Inhibition of Gi/o with pertussis toxin obliterated both acute and delayed A1AR-mediated renal protection. In contrast to renal protection with delayed ischemic preconditioning, NOS activity was not induced with delayed A1AR-mediated renal protection. Therefore, transient activation of renal A1AR led to acute as well as delayed protective effects against renal IR injury via distinct signaling pathways.
