Upregulation of iron regulatory proteins and divalent metal transporter-1 isoforms in the rat hippocampus after kainate induced neuronal injury

Abstract

Iron regulatory proteins (IRP1 and IRP2) bind to iron response elements (IRE) on specific mRNAs, to affect the translation of many proteins involved in iron metabolism. An increase in iron levels and divalent metal transporter-1 (DMT1) expression have been observed in the rat hippocampus after excitotoxic injury induced by kainate, but thus far, it is not known whether these could be associated with changes in IRPs. The present study was therefore carried out to elucidate the expression of IRP1 or IRP2 and the IRE or non-IRE forms of DMT1 (DMT1 or -IRE DMT1) in the hippocampus after neuronal injury induced by kainate. A sustained upregulation of IRP1, IRP2, DMT1 and -IRE DMT1 protein was detected in the lesioned hippocampus by western blot and immunohistochemical analyses up to 2 months post-injection. Double immunofluorescence labeling showed that IRP1, IRP2, DMT1 and - IRE DMT1 were mostly expressed in GFAP positive astrocytes. The increased IRP expression could lead to increased expression of the +IRE form of DMT1. On the other hand, the increased expression of the -IRE DMT1 indicates that IRPs are unlikely to be only factor determining the expression of DMT1. It is postulated that transcription factors acting on putative AP-1, NF-κB binding sites, or γ-interferon responsive elements on the DMT1 promoter may also play a role in upregulating the expression of the transporter. This could lead to increased iron influx into the brain areas undergoing neurodegeneration, and might be a factor contributing to neuronal damage after the initial excitotoxic injury. © Springer-Verlag 2005.