Epigenetic Regulation of Ferroportin in Primary Cultures of the Rat Blood-Brain Barrier

Helgudottir, Steinunn Sara; Routhe, Lisa Juul; Burkhart, Annette; Jønsson, Katrine; Pedersen, Inge Søkilde; Lichota, Jacek; Moos, Torben

doi:10.1007/s12035-020-01953-y

Cited by 9 publications

(16 citation statements)

References 75 publications

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“…Enzyme-linked immunosorbent assay (ELISA) was used to measure the amount of TfR, GLUT1 and CD98hc in isolated brain capillaries after VPA treatment to evaluate protein expression at the level of the BBB 24 . In order to account for varying protein concentrations in each sample, the total protein concentration was measured using BCA protein assay kit as previously described 13 . Each sample was lysed using 90 µL N-per Neuronal protein extraction buffer supplemented with cOmplete Mini protease inhibitor.…”

Section: Elisamentioning

confidence: 99%

“…VPA induces epigenetic changes by inhibiting histone deacetylase, which further enables acetylation of histones and consequently gene transcription 12 . We have previously shown that the expression of ferroportin, another iron-transporting molecule (aka SLC40A1 or IREG1), is epigenetically upregulated in isolated rat BCECs in response to VPA treatment 13 .…”

Section: Introductionmentioning

confidence: 99%

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Epigenetic upregulation by valproic acid of transferrin receptor 1, and not glucose transporter 1 or CD98hc, at the blood-brain barrier

Helgudottir

Johnsen²,

Routhe

et al. 2022

Preprint

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BackgroundThe objectives of the present study were to investigate whether the expression of transferrin receptor 1 (TfR1), glucose transporter 1 (Glut1), or Cluster of Differentiation 98 Heavy Chain (CD98hc) is epigenetically regulated in brain capillary endothelial cells (BCECs) denoting the blood-brain barrier (BBB).MethodsThe expression of these targets was investigated both in vitro and in vivo following treatment with the histone deacetylase inhibitor (HDACi) valproic acid (VPA). Mice were injected intraperitoneally with VPA followed by analysis of isolated brain capillaries, and the capillary depleted brain samples. Brain tissue, isolated brain capillaries, and cultured primary endothelial cells were analyzed by RT-qPCR, immunolabeling and ELISA for expression of TfR1, Glut1 and CD98hc. We also studied the vascular targeting in VPA-treated mice injected with monoclonal anti-transferrin receptor (Ri7) conjugated with 1.4 nm gold nanoparticles. ResultsValidating the effects of VPA on gene transcription in BCECs, transcriptomic analysis identified 24,371 expressed genes, of which 305 were differentially expressed with 192 upregulated and 113 downregulated genes. In vitro using BCECs co-cultured with glial cells, the mRNA expression of Tfrc was significantly higher after VPA treatment for 6 h with its expression returning to baseline after 24 h. Conversely, the mRNA expression of Glut1 and Cd98hc was unaffected by VPA treatment. In vivo, the TfR1 protein expression in brain capillaries increased significantly after treatment with both 100 mg/kg and 400 mg/kg VPA. Conversely, VPA treatment did not increase GLUT1 or CD98hc. Using ICP-MS-based quantification, the brain uptake of nanogold conjugated anti-TfR1 antibodies was non-significant in spite of increased expression of TfR1. ConclusionsWe report that VPA treatment upregulates TfR1 at the BBB both in vivo and in vitro in isolated primary endothelial cells. In contrast, VPA treatment does not influence the expression of GLUT1 and CD98hc. The increase in the overall TfR1 protein expression however does not increase transport of TfR-targeted monoclonal antibody and indicates that targeted delivery using the transferrin receptor should aim for increased mobilization of already available transferrin receptor molecules to improve trafficking through the BBB.

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Section: Elisamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Epigenetic upregulation by valproic acid of transferrin receptor 1, and not glucose transporter 1 or CD98hc, at the blood-brain barrier

Helgudottir

Johnsen²,

Routhe

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

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“…This mechanism, which is also involved in the reduction of the inflammatory response, may prevent excessive iron retention in macrophages during the resolution phase of inflammation when local iron deficiency in the microenvironment may jeopardy tissue repair [31]. Additionally, epigenetic regulation of FPN has been recently described in primary cultures of endothelial cells of the rat blood-brain barrier [32].…”

Section: Ferroportinmentioning

confidence: 99%

Iron Availability in Tissue Microenvironment: The Key Role of Ferroportin

Gammella

Correnti

Cairo

et al. 2021

IJMS

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Body iron levels are regulated by hepcidin, a liver-derived peptide that exerts its function by controlling the presence of ferroportin (FPN), the sole cellular iron exporter, on the cell surface. Hepcidin binding leads to FPN internalization and degradation, thereby inhibiting iron release, in particular from iron-absorbing duodenal cells and macrophages involved in iron recycling. Disruption in this regulatory mechanism results in a variety of disorders associated with iron-deficiency or overload. In recent years, increasing evidence has emerged to indicate that, in addition to its role in systemic iron metabolism, FPN may play an important function in local iron control, such that its dysregulation may lead to tissue damage despite unaltered systemic iron homeostasis. In this review, we focus on recent discoveries to discuss the role of FPN-mediated iron export in the microenvironment under both physiological and pathological conditions.

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“…Epigenetic regulation can occur on the DNA itself, or on histones as posttranscriptional regulation, which include acetylation, methylation, phosphorylation (191). DNA methylation is a rigid form for transcriptional silencing that results in a long term alteration of the gene expression, and is currently the best characterized covalent modification of DNA (192)(193)(194). Actively transcribed genes do therefore contain low DNA methylation percentage and vice versa (188,194).…”

Section: Epigenetic Regulation At the Blood-brain Barriermentioning

confidence: 99%

“…DNA methylation is a rigid form for transcriptional silencing that results in a long term alteration of the gene expression, and is currently the best characterized covalent modification of DNA (192)(193)(194). Actively transcribed genes do therefore contain low DNA methylation percentage and vice versa (188,194). DNA methylation is the addition of a methyl group to the 5-carbon position of cytosine catalyzed by methyltransferases (188,194,195).…”

Section: Epigenetic Regulation At the Blood-brain Barriermentioning

confidence: 99%

Expressional prerequisites for targeted drug delivery to the pathological brain

Helgudottir

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Epigenetic Regulation of Ferroportin in Primary Cultures of the Rat Blood-Brain Barrier

Cited by 9 publications

References 75 publications

Epigenetic upregulation by valproic acid of transferrin receptor 1, and not glucose transporter 1 or CD98hc, at the blood-brain barrier

Epigenetic upregulation by valproic acid of transferrin receptor 1, and not glucose transporter 1 or CD98hc, at the blood-brain barrier

Iron Availability in Tissue Microenvironment: The Key Role of Ferroportin

Expressional prerequisites for targeted drug delivery to the pathological brain

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