Regulation of endoplasmic reticulum stress in rat cortex by p62/ZIP through the Keap1-Nrf2-ARE signalling pathway after transient focal cerebral ischaemia

Primary objective: p62/ZIP as the autophagy receptor can transport the misfolded proteins to a macroautophagy-lysosome system for degradation and also create a positive feedback loop between p62/ZIP and Nrf2. However, the role of p62/ZIP on cerebral ischaemia is unclear. The aim of this study was to evaluate the role of p62/ZIP in the regulation of endoplasmic reticulum(ER) stress induced by cerebral ischaemia/reperfusion. Research design: Different ischemic periods were designed by transient middle cerebral artery occlusion (tMCAO) using the suture method. Methods and procedures: At 24 hours after reperfusion, the ischaemic brain tissue was studied histologically and biochemically for autophagic, ER stress and Keap1-Nrf2-ARE signalling pathway markers. Main outcomes and results: Prolongation of ischaemia significantly increased the cortical injury observed in rats and was associated with a gradual increase in the protein expression of ubiquitin-aggregates, Grp78, GADD153/CHOP and p62/ZIP. Autophagy marker Atg12-Atg5 and LC3-PE increased and then decreased. Moreover, p62/ZIP mRNA expression increased and then decreased and was consistent with Nrf2 activation. Conclusions: p62/ZIP not only plays a key role in scavenging protein aggregates during autophagy, but it may also be involved in preventing oxidative injury and alleviating ER stress through the Keap1-Nrf2-ARE signalling pathway during cerebral ischaemia/reperfusion injury.