Sodium vitamin C cotransporter SVCT2 is expressed in hypothalamic glial cells

García, María de los Ángeles Olivares; Salazar, Katterine; Millán, Carola; Rodríguez, Federico; Montecinos, Hernán; Caprile, Teresa; Silva, Cármen; Cortés, Christian; Reinicke, Karin; Vera, Juan Carlos; Aguayo, Luis G.; Olate, Juan; Molina, Benedicto; Nualart, Francisco

doi:10.1002/glia.20133

Cited by 98 publications

(100 citation statements)

References 60 publications

(86 reference statements)

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“…In agreement with previous in situ hybridization (Astuya et al, 2005;García et al, 2005) and immunocytochemical studies, the SVCT2 was not present in endothelial cells lining cortical capillaries in the mouse, either by direct staining or by immunoblotting. However, when the cells were purified and placed into culture, the SVCT2 was readily detected after several days and was associated with ascorbate transport rates comparable to immortalized endothelial cell lines.…”

Section: Discussionsupporting

confidence: 92%

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Development of ascorbate transporters in brain cortical capillary endothelial cells in culture

Qiao

May

2008

Brain Research

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Ascorbic acid in its reduced form is not transported across the capillary endothelial cell blood-brain barrier. This is thought to be due to absence of the SVCT2, a specific transporter for ascorbate. To assess this directly we prepared primary cultures of mouse cortical microvascular endothelial cells. When still in the capillaries, these cells did not express the SVCT2 protein as assessed by immunocytochemistry and by immunoblotting. However, during several days in culture, they developed SVCT2 expression and showed ascorbate transport rates comparable to those in immortalized endothelial cell lines. SVCT2 expression was inversely proportional to cell density, was enhanced by culture at low physiologic plasma ascorbate concentrations, was inhibited by ascorbate concentrations expected in the brain interstitium, and was stimulated by cobalt ions. Expression of the SVCT2 was associated with ascorbate-dependent maturation and release of type IV collagen by the cells in culture. Although the SVCT2 is induced by culture of cortical capillary endothelial cells, its absence in vivo remains perplexing, given the need for intracellular ascorbate to facilitate type IV collagen maturation and release by endothelial cells. SectionStructural Organization of the Brain Keywords SVCT2; ascorbate transport; cobalt, collagen; cortical capillary endothelial cells Vitamin C, or ascorbic acid, is an important antioxidant and enzyme co-factor in the central nervous system, where it has several functions, including antioxidant protection (Rice2000), peptide amidation (Eipper et al., 1983), myelin formation (Eldridge et al., 1987), enhancement of synaptic activity (Qiu et al., 2007), and protection against glutamate toxicity (Rebec et al., 1994). In contrast to other organs, however, very little ascorbate appears to enter the brain directly across capillary endothelial cells forming the blood-brain barrier (BBB). Rather, the vitamin is transported from the blood into the cerebrospinal fluid through the choroid plexus (Agus et al., 1997;Spector1977) and by specialized cells lining the third ventricle . Plasma concentrations of ascorbate are 30-60 µM, and these are increased to 200-400 µM in the cerebrospinal fluid through this mechanism (Reiber et al., 1993;Spector et al., 1973). Transport of ascorbate into neurons further increases the gradient, since neurons contain *Corresponding author: Dr. James May, 7465 Medical Research Building IV, Vanderbilt University School of Medicine, Nashville, TN 37232-0475. Tel. (615) 936-1653; Fax: (615) 936-1667. E-mail: james.may@vanderbilt.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal d...

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 92%

Development of ascorbate transporters in brain cortical capillary endothelial cells in culture

Qiao

May

2008

Brain Research

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“…Many studies indicate that SVCT2 is a transporter that is preferentially expressed in neurons from different areas in the adult brain, such as the cortex, hippocampus, hypothalamus, and cerebellar precursors [1,[7][8][9][10][11]. SVCT2 mediates uptake of AA, an important molecule for antioxidant defense and general metabolic needs of neurons.…”

Section: Distribution and Function Of Svct2 In The Adult Brainmentioning

confidence: 99%

“…SVCT2 mediates uptake of AA, an important molecule for antioxidant defense and general metabolic needs of neurons. Although SVCT2 was originally thought to be a neuronal transporter, there is increasing evidence demonstrating its expression in glial cells in the CNS [4,7,8,10,[12][13][14]. Indeed, SVCT2 has been reported in cortical microglia, where its function remains unknown [10].…”

Section: Distribution and Function Of Svct2 In The Adult Brainmentioning

confidence: 99%

“…Indeed, SVCT2 has been reported in cortical microglia, where its function remains unknown [10]. In hypothalamic tanycytes, it may participate in maintaining the high parenchymal concentrations of vitamin C that characterize this region [8]. Furthermore, in choroid plexus cells, it facilitates entry of AA into the brain through the blood-cerebrospinal fluid (CSF) barrier [4,7,10,12].…”

Section: Distribution and Function Of Svct2 In The Adult Brainmentioning

confidence: 99%

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Vitamin C Transporter (SVCT2) Distribution in Developing and Adult Brains

Ferrada¹,

Salazar²,

Santander³

2017

Vitamin C

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Vitamin C is the major antioxidant molecule in the central nervous system (CNS), reaching concentrations of 10 mM in neurons and 400 μM in the cerebrospinal fluid (CSF). Uptake of vitamin C by brain cells is performed through the co-transporter of ascorbic acid and sodium isoform 2, SVCT2, which is expressed in cells from the choroid plexus, neurons, oligodendrocytes, and ependymal cells. SVCT2 expression has also been described in cells at the neurogenic niche, specifically in proliferative type C cells. In this chapter, we will describe recently published studies of SVCT2 expression during brain development and define its polarization in cells from the radial glia (neuronal precursors within the CNS) and vitamin C-mediated effects in regulating genes associated with the maintenance of CNS stem cell pluripotency. We will discuss the differential biological effect that vitamin C generates in neurons versus astrocytes and how the oxidized form of vitamin C, dehydroascorbic acid (DHA), produced by neurons in conditions of oxidative stress must leave this cell to be incorporated by astrocytes. In this context, we will discuss recent literature, which shows that DHA regulates glycolytic metabolism in neurons. In parallel, we will analyze vitamin C recycling by astrocytes, which reduce DHA into ascorbic acid (AA), increasing the antioxidant potential of the brain. Data discussed in this chapter will provide an updated view of SVCT2 distribution in the brain and will also describe how vitamin C recycling participates in normal or pathological brain function.

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Sodium‐dependent vitamin C transporter 2 (SVCT2) is necessary for the uptake of L‐ascorbic acid into Schwann cells

Gess

Lohmann

Halfter

et al. 2009

Glia

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Ascorbic acid has been shown to be an essential component for in vitro myelination and to improve the clinical and pathological phenotype of a mouse model of Charcot-Marie-tooth disease 1A. The mechanism of ascorbic acid uptake into peripheral nerves, however, has not been addressed so far. Hence, we studied the expression and activity of sodium-dependent vitamin C transporters 1 and 2 (SVCT1 and 2) in the peripheral nervous system. Using immunohistochemistry, immunoblotting, and reverse transcription PCR, we could show that SVCT1 and 2 were differentially expressed in myelinated peripheral nerve fibers and Schwann cell (SC) cultures. SVCT1 was expressed at very low levels confined to the axons, whereas SVCT2 was highly expressed both in the axons and in the SCs. SVCT2 was localized particularly in SC compartments of uncompacted myelin. Uptake assays using (14)C-labeled ascorbic acid showed transport of ascorbic acid into SC cultures. Ascorbic acid transport was dependent on the concentration of sodium, magnesium, and calcium in the extracellular medium. Treatment with the flavonoid phloretin, a known inhibitor of SVCT1 and 2, and specific RNA interference with SVCT2 caused significant reductions in ascorbic acid uptake into SCs. Phloretin-inhibited uptake of ascorbic acid was further shown in freshly dissected, cell-culture-naïve rat sciatic nerves. These results provide evidence for the first time that uptake of ascorbic acid in the peripheral nervous system is crucially dependent on the expression and activity of SVCT2.

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Sodium vitamin C cotransporter SVCT2 is expressed in hypothalamic glial cells

Cited by 98 publications

References 60 publications

Development of ascorbate transporters in brain cortical capillary endothelial cells in culture

Development of ascorbate transporters in brain cortical capillary endothelial cells in culture

Vitamin C Transporter (SVCT2) Distribution in Developing and Adult Brains

Sodium‐dependent vitamin C transporter 2 (SVCT2) is necessary for the uptake of L‐ascorbic acid into Schwann cells

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