Overexpression of Growth Differentiation Factor 15 Reduces Neuronal Cell Damage Induced by Oxygen-Glucose Deprivation/Reoxygenation via Inhibiting Endoplasmic Reticulum Stress-Mediated Ferroptosis.

Abstract

Growth differentiation factor 15 (GDF15) can be induced under various stress conditions. This study aimed to explore the role of GDF15 in oxygen-glucose deprivation/reoxygenation (OGD/R)-induced HT22 cells. OGD/R was employed to induce the HT22 cell model, and GDF15 expression was upregulated via transfection. Subsequently, the effects on inflammatory factors, oxidative stress markers, apoptosis-related proteins, and ferroptosis markers were detected. Relevant indicators were evaluated using techniques such as ELISA, probes, flow cytometry, and western blotting. Furthermore, changes in these phenotypes under the influence of the endoplasmic reticulum (ER) stress agonist tunicamycin (TM) were evaluated. The result showed that GDF15 was significantly up-regulated in OGD/R-treated HT22 cells. Overexpression of GDF15 significantly reduced the levels of inflammatory factors tumor necrosis factor-α, IL (interleukin)-1β, and IL-6, inhibited the production of reactive oxygen species and MDA, and improved activity of superoxide dismutase and GSH-Px. Flow cytometry and western blotting results showed that GDF15 overexpression significantly reduced cell apoptosis, reduced caspase3 activity, and regulated the expression of Bcl2 and Bax. In addition, overexpression of GDF15 reduces the levels of ferroptosis markers by inhibiting ER stress. ER stress inducer TM can reverse the protective effects of GDF15 overexpression and promote inflammation, oxidative stress, and apoptosis. This study shows that overexpression of GDF15 reduces OGD/R-induced HT22 cell damage, and ER stress-mediated ferroptosis is included in the regulatory mechanisms. This provides a theoretical basis for GDF15 as a new target for the treatment of cerebral ischemia-reperfusion injury.