Journal
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
Volume 41, Issue 5, Pages 3051-3062Publisher
SPANDIDOS PUBL LTD
DOI: 10.3892/ijmm.2018.3469
Keywords
ischemia; reperfusion injury; Sertoli cell; ferroptosis; lipid reactive oxygen species; iron; ferroportin
Categories
Funding
- National Natural Science Foundation of China [81373787]
- Hebei Provincial Natural Science Fund [H2013201139]
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Sertoli cell death contributes to spermatogenesis impairment, which is associated with male infertility. Testicular ischemia-reperfusion (I/R) injury induces the cell death of germ cells and Sertoli cells, whereas inhibition of cell death ameliorates acute testicular I/R damage. The aim of the present study was to investigate the mechanism of I/R stress-induced cell death in TM4 cells. Oxygen-glucose deprivation and reoxygenation (OGD/R) was demonstrated to induce I/R injury and cell death in TM4 cells. Cell death was blocked by the reactive oxygen species (ROS) inhibitor N-acetylcysteine, as well as lipid peroxidation inhibitors Liproxstatin-1 and iron chelator deferoxamine; however, inhibitors of apoptosis, necrosis or autophagy had no effect. It was also demonstrated that iron and lipid ROS levels were elevated in I/R injury and that mitochondria decreased in size and increased in membrane density, which is indicative of ferroptosis. Furthermore, the generation of lipid ROS suggests iron accumulation and glutathione (GSH) depletion. The expression of ferroportin (Fpn) protein and mRNA was decreased in TM4 cells. Notably, overexpression of Fpn inhibited ferroptosis, lipid ROS generation and iron accumulation. In addition, GSH-dependent peroxidase 4 (GPX4) was inactivated via GSH depletion following I/R injury, whereas GPX4 activation blocked I/R-induced ferroptosis by reducing lipid ROS levels. The mitogen-activated protein kinase (MAPK) pathway was also investigated in the present study; it was observed that I/R-induced ferroptosis was blocked by inhibiting p38 MAPK activation. The results of the present study demonstrate that ferroptosis is a pervasive and dynamic type of cell death induced by OGD/R injury in Sertoli cells. This may provide a novel insight into the application of cytoprotection in testicular I/R damage-induced cell loss.
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