ZNT-1 Expression Reduction Enhances Free Zinc Accumulation in Astrocytes After Ischemic Stroke

Excess intracellular zinc has been implicated in ischemic brain cell death. We previously reported that extracellular zinc increases intracellular free zinc level only in hypoxic astrocytes but not in normoxia astrocytes. However, the underlying mechanisms remain to be elucidated. Zinc transporters ZnTs and ZIPs mediate intracellular zinc efflux and extracellular zinc influx. In the present study, we determined the effect of hypoxia/reoxygenation on ZnT-1 and ZIP-1. Hypoxia/reoxygenation did not change the ZIP-1 level in astrocytes. Remarkably, hypoxia/reoxygenation dramatically decreased ZnT-1 expression, which can be difficult to reverse by the addition of extracellular zinc, although extracellular zinc treatment significantly increased ZnT-1 level at normoxia. These results suggest that hypoxia/reoxygenation blocked zinc efflux, whereas zinc influx may be at a similar level to that in normoxia, providing a novel mechanism for intracellular free zinc accumulation after ischemic stroke.