TI - Shear stress induces Nrf2 nuclear translocation through a PI3K -dependent pathway . AB - Many previous studies implied that Nrf2 activation is mediated through the PI3K pathway [36,37,53] . Since shear stress is known to activate the PI3K pathway , we speculated that PI3K might participate in shear-induced Nrf2 nuclear translocation . As anticipated , we found that shear-induced Nrf2 nuclear translocation was suppressed by pretreating HUVECs with LY294002 , a PI3K inhibitor (Figure 2A) , suggesting that the PI3K pathway plays a key role in shear-induced Nrf2 activation . It was found that protein kinase C ( PKC ) PHOSphorylates Nrf2 and regulates concomitant ARE -mediated transcription in response to oxidative stress [38,39] . A recent study showed that the anti-inflammatory activity of Phellinus linteus ( an orange-colored mushroom ) is mediated through PKCdelta/Nrf2/ARE signaling that leads to the upregulation of HO-1 [54] . These findings suggest that PKC may play a role in shear-induced Nrf2 nuclear translocation . To test this hypothesis , calphostin C ( a PKC inhibitor ) was used to pretreat HUVECs prior to the shear stress experiment . Pre-exposure to calphostin C did not affect the basal level of nuclear Nrf2 protein but significantly attenuated shear-induced Nrf2 nuclear translocation ( Figure 2B ) , indicating that PKC is involved in the nuclear translocation of Nrf2 in response to shear stress . Chen et al .determined that dietary chemopreventive compounds induce Nrf2 translocation through MAPK pathways [55] . Owuor et al .also reported similar pathways for Nrf2 translocation under chemical stress [56] . Many MAPK family proteins , including p38 and JNK , are activated by shear stress stimulation . It is likely that the translocation of Nrf2 under shear stress conditions is regulated by the MAPK pathway . However , the use of SB203580 ( a p38-specific inhibitor ) and SP600125 ( a JNK inhibitor ) did not attenuate the translocation of Nrf2 ( Figs 2C & lt @@@@@ gt 2D ) . This suggests that even though MAPK pathways are activated by shear stress , p38 and JNK are not involved in shear-induced Nrf2 translocation .