Abstract
In the light of hepatocyte growth factor (HGF) the inhibiting role on the expression of hepcidin, we hypothesized that HGF might be able to reduce cell and tissue iron by increasing ferroportin 1 (Fpn1) content and Fpn1-mediated iron release from cells and tissues. The hypothesized ability of HGF to reduce iron might be one of the mechanisms associated with its neuroprotective action under the conditions of ischemia/reperfusion (I/R). Here, we investigated the effects of HGF on the expression of hepcidin as well as transferrin receptor 1 (TfR1), divalent metal transporter 1 (DMT1), Fpn1, ferritin and iron regulatory proteins (IRPs) in oxygen-glucose deprivation and reoxygenation (OGD/R)-treated PC12 cells by real-time PCR and Western blot analysis. We demonstrated that HGF could completely reverse the OGD/R-induced reduction in Fpn1 and IRP1 expression and increase in ferritin light chain protein and hepcidin mRNA levels in PC12 cells. It was concluded that HGF protects PC12 cells against OGD/R-induced injury mainly by reducing cell iron contents via the up-regulation of Fpn1 and increased Fpn1-mediated iron export from cells. Our findings suggested that HGF may also be able to ameliorate OGD/R or I/R-induced overloading of brain iron by promoting Fpn1 expression.
Highlights
Hepatocyte growth factor (HGF) is a pleiotropic cytokine [1,2]
We investigated the effects of HGF on the expression of hepcidin as well as on cell-iron importers transferrin receptor 1 (TfR1) and divalent metal transporter 1 (DMT1), cell-iron exporter ferroportin 1 (Fpn1), cell-iron storage protein ferritin, and iron regulatory protein 1 and 2 (IRP1 and 2) in oxygen-glucose deprivation and reoxygenation (OGD/R)-treated PC12 cells
The expression of Fpn1 in the cells co-treated with HGF+OGD/R was shown to be significantly lower than that in the cells treated with OGD/R only and showed no difference from that in the cells treated by 40 ng/ml of HGF only (Figure 2C), indicating that HGF could completely restore the effect of OGD/R on Fpn1
Summary
Hepatocyte growth factor (HGF) is a pleiotropic cytokine [1,2]. The binding of HGF to its unique tyrosine kinase receptor, c-Met, induces activation of Met tyrosine kinase and the autophosphorylation of tyrosine residues in Met [3,4]. A number of studies have demonstrated that HGF markedly improves recovery in learning and memory dysfunction and disruption of the blood–brain barrier induced by cerebral ischemia in microsphere-embolized rats [9], attenuates neurological deficits in a rat transient middle cerebral artery occlusion (MCAO) model [10], induces long-term neuroprotection and stroke recovery in male C57/BL6N mice [11], prevents the delayed death of hippocampal neurons in Mongolian gerbils with transient forebrain ischemia [12], protects hippocampal neurons from apoptotic cell death after transient forebrain ischemia in male Wistar rats [13], reduces infarct size and the number of TUNEL-positive cells, promotes the neurogenesis, angiogenesis, and synaptogenesis, and inhibits fibrotic change in brains in rats subjected to transient middle cerebral artery occlusion (tMCAO) [14]. The mechanisms involved in the neuroprotective action of HGF have not been completely elucidated
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