The NFATC2/Nrf2 cascade regulates spinal cord ischemia-reperfusion injury by controlling inflammation, apoptosis and oxidative stress

Spinal cord ischemia/reperfusion (IR) injury (SCII) can cause major autonomic, sensory, and motor damage and loss. The upregulation of Nrf2, a primary orchestrator of the oxidative stress response, has beneficial effects in SCII. Here, we aimed to uncover a SCII-related transcription factor that is able to elevate Nrf2 expression. Rat PC12 cells were subjected to treatment with oxygen-glucose deprivation/ reoxygenation (OGD/R) to induce an in vitro neuronal IR injury model. A rat model of SCII was established by blocking the left common carotid artery and aortic arch in SD rats. Cell viability and apoptosis were assessed by the CCK-8 assay and flow cytometry, respectively. IL-1b and TNF-a levels were detected by ELISA. The oxidative stress was tested by assessing ROS and MDA contents and SOD and GSH-Px activity. The NFATC2/Nrf2 relationship was predicted by bioinformatic analysis and validated by ChIP and luciferase reporter assays. Nrf2 and NFATC2 levels were reduced in PC12 cells after OGD/R treatment. Nrf2 increase significantly attenuated OGD/R-triggered inflammation, apoptosis and oxidative stress in PC12 cells. Moreover, Nrf2 increase alleviated spinal cord pathological changes, inflammation, apoptosis and oxidative stress in rats after SCII. Mechanistically, NFATC2 could activate Nrf2 transcription and promote its expression. Nrf2 reduction exerted a counteracting impact on NFATC2's anti-inflammation, anti-apoptosis and anti-oxidative stress functions in PC12 cells under OGD/R conditions. Our study demonstrates that the NFATC2/Nrf2 cascade has a regulatory capacity in inflammation, apoptosis and oxidative stress after SCII. (c) 2024 The Author(s). Published by Elsevier BV on behalf of The Japanese Society for Regenerative Medicine. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).