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Selective Activation of Alpha 7 Nicotinic Receptor Antagonizes Apoptosis in Renal Cells via Nrf2 Signaling
Authors:  Tao Huang, M.M., Zhen Dong, M.M., Yanwei Cao, M.D., Qinghai Wang, M.D., and Xunbo Jin, M.D.
  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.
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.
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.
Keywords:  α7 nicotinic cholinergic receptor; α7nAChR; alpha7 nicotinic acetylcholine receptor; alpha7nAChR; apoptosis; cholinergic agonists; epithelial renal cells; ischemia-reperfusion injury; nicotinic agonists; Nrf2; nuclear factor E2-related factor 2; PHA568487; reperfusion injury
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