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Protein Kinase C and G_i/o Proteins Are Involved in Adenosine- and Ischemic Preconditioning—Mediated Renal Protection

Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York.

Correspondence to Dr. H. Thomas Lee, Department of Anesthesiology, Columbia Presbyterian Medical Center, P&S Box 46, 630 West 168th Street, New York, NY 10032. Phone: 212-305-0586; Fax: 212-305-8980; E-mail: tl128{at}columbia.edu

Abstract. Renal ischemic reperfusion (IR) injury is a significant clinical problem in anesthesia and surgery. Recently, it was demonstrated that both renal ischemic preconditioning (IPC) and systemic adenosine pretreatment protect against renal IR injury. In cardiac IPC, pertussis toxin-sensitive G-proteins (i.e., G_i/o), protein kinase C (PKC), and ATP-sensitive potassium (K⁺ _ATP) channels are implicated in this protective signaling pathway. The aim of this study was to elucidate the signaling pathways that are responsible for renal protection mediated by both IPC and adenosine pretreatment. In addition, because A₁ adenosine receptor antagonist failed to block renal IPC, whether activation of bradykinin, muscarinic, or opioid receptors can mimic renal IPC was tested because these receptors have been implicated in cardiac IPC. Rats were acutely pretreated with chelerythrine or glibenclamide, selective blockers of PKC and K⁺ _ATP channels, respectively, before IPC or adenosine pretreatment. Some rats were pretreated with pinacidil (K⁺ _ATP channel opener), bradykinin, methacholine, or morphine before renal ischemia. Twenty-four h later, plasma creatinine was measured. Separate groups of rats received pertussis toxin intraperitoneally 48 h before being subjected to the above protective protocols. IPC and adenosine pretreatment protected against renal IR injury. Pretreatment with pertussis toxin and chelerythrine abolished the protective effects of both renal IPC and adenosine. However, glibenclamide pretreatment had no effect on either renal IPC or adenosine-induced renal protection, indicating no apparent role for K⁺ _ATP channels. Moreover, pinacidil, bradykinin, methacholine, and morphine failed to protect renal function. Therefore, the conclusion is that cellular signal transduction pathways of renal IPC and adenosine pretreatment in vivo involve G_i/o proteins and PKC but not K⁺ _ATP channels. Unlike cardiac IPC, bradykinin, muscarinic, and opioid receptors do not mediate renal IPC.

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