OBJECTIVE: Both the selective agonists of α7 nicotinic cholinergic receptor (α7nAChR) and the activators of nuclear factor E2-related factor 2 (Nrf2) are promising therapeutic agents for renal ischemia-reperfusion (IR) injury. We aimed to investigate the relationship of α7nAChR activation and Nrf2 in antagonizing renal IR injury. STUDY DESIGN: Using hypoxia-reoxygenation (HR) in the renal epithelial cell line (HK2 cells) as a model of renal IR injury, we examined the effects of an α7nAChR agonist, PHA568487, on the HR injury-induced apoptosis and the apoptotic signaling, and the role of Nrf2 in the effects of the α7nAChR agonist. RESULTS: The selective agonist of α7nAChR, PHA568487, dramatically attenuated the HR injury-induced apoptotic cell deaths of HK2 cells. The agonist also significantly suppressed the HR-induced elevation of mRNA and protein levels of caspase-3 and Bax and enhanced the expression of the anti-apoptotic molecule Bcl-2. The application of an Nrf2 inhibitor, ML385, significantly but incompletely blocked the effects of PHA568487 on apoptosis and the expression of the apoptotic signaling molecules. CONCLUSION: These results indicate that the selective activation of α7nAChR exerts significant anti-apoptotic effects in the renal cells via antagonizing the apoptotic signaling and activating the anti-apoptotic signaling, which is partially mediated by the Nrf2 transcription factor. Thus, the activation of α7nAChR may exert strong anti-apoptotic effect during renal IR injury through Nrf2-dependent and independent mechanisms. © Science Printers and Publishers, Inc.