Abstract
Fumaric acid esters are used to treat psoriasis, an inflammatory skin disease characterized by keratinocyte proliferation. Inflammation and proliferation are hallmarks of retinal disease; hence, fumaric acid esters may have therapeutic value in retinal pathology. In diseased retinas, Müller glial cells (MCs) undergo reactive gliosis, a hyperproliferative state. MCs take up folate, a vitamin necessary for cell proliferation, via the proton-coupled folate transporter (PCFT). Here we examined the effect of monomethylfumarate (MMF), the active metabolite of fumaric acid esters, on expression and function of PCFT in MCs. Primary MCs, isolated from neonatal mouse retinas, were treated with MMF, and PCFT function was monitored by measuring uptake of radiolabeled methyltetrahydrofolate (MTF) at pH 5.5. Dose-response and time-course analyses were performed to identify optimal conditions for maximal effect. The influence of MMF treatment on kinetic parameters of PCFT was studied, and PCFT expression was analyzed at the mRNA and protein level. MTF uptake in MCs decreased by ̃50% following 18 h treatment with 1 mM MMF. This effect was specific to fumaric acid esters. MMF treatment decreased the maximal velocity of the transporter without altering substrate affinity. The decrease in PCFT function following MMF treatment was accompanied by attenuated PCFT expression. This is the first report that an antipsoriatic compound can regulate folate transport in MCs and may have potential for the treatment of reactive gliosis in retinal disease.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 333-342 |
| Number of pages | 10 |
| Journal | Glia |
| Volume | 60 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 1 2012 |
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Keywords
- Folic acid
- Fumaric acid esters
- Mouse
- Müller cell gliosis
- Vitamin transport
ASJC Scopus subject areas
- Neurology
- Cellular and Molecular Neuroscience
Cite this
Regulation of proton-coupled folate transporter in retinal Müller cells by the antipsoriatic drug monomethylfumarate. / Bozard, B. Renee; Chothe, Paresh P.; Tawfik, Amany; Williams, Cory; Fulzele, Sadanand; Prasad, Puttur D.; Martin, Pamela M.; Ganapathy, Vadivel; Smith, Sylvia B.
In: Glia, Vol. 60, No. 3, 01.03.2012, p. 333-342.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Regulation of proton-coupled folate transporter in retinal Müller cells by the antipsoriatic drug monomethylfumarate
AU - Bozard, B. Renee
AU - Chothe, Paresh P.
AU - Tawfik, Amany
AU - Williams, Cory
AU - Fulzele, Sadanand
AU - Prasad, Puttur D.
AU - Martin, Pamela M.
AU - Ganapathy, Vadivel
AU - Smith, Sylvia B.
PY - 2012/3/1
Y1 - 2012/3/1
N2 - Fumaric acid esters are used to treat psoriasis, an inflammatory skin disease characterized by keratinocyte proliferation. Inflammation and proliferation are hallmarks of retinal disease; hence, fumaric acid esters may have therapeutic value in retinal pathology. In diseased retinas, Müller glial cells (MCs) undergo reactive gliosis, a hyperproliferative state. MCs take up folate, a vitamin necessary for cell proliferation, via the proton-coupled folate transporter (PCFT). Here we examined the effect of monomethylfumarate (MMF), the active metabolite of fumaric acid esters, on expression and function of PCFT in MCs. Primary MCs, isolated from neonatal mouse retinas, were treated with MMF, and PCFT function was monitored by measuring uptake of radiolabeled methyltetrahydrofolate (MTF) at pH 5.5. Dose-response and time-course analyses were performed to identify optimal conditions for maximal effect. The influence of MMF treatment on kinetic parameters of PCFT was studied, and PCFT expression was analyzed at the mRNA and protein level. MTF uptake in MCs decreased by ̃50% following 18 h treatment with 1 mM MMF. This effect was specific to fumaric acid esters. MMF treatment decreased the maximal velocity of the transporter without altering substrate affinity. The decrease in PCFT function following MMF treatment was accompanied by attenuated PCFT expression. This is the first report that an antipsoriatic compound can regulate folate transport in MCs and may have potential for the treatment of reactive gliosis in retinal disease.
AB - Fumaric acid esters are used to treat psoriasis, an inflammatory skin disease characterized by keratinocyte proliferation. Inflammation and proliferation are hallmarks of retinal disease; hence, fumaric acid esters may have therapeutic value in retinal pathology. In diseased retinas, Müller glial cells (MCs) undergo reactive gliosis, a hyperproliferative state. MCs take up folate, a vitamin necessary for cell proliferation, via the proton-coupled folate transporter (PCFT). Here we examined the effect of monomethylfumarate (MMF), the active metabolite of fumaric acid esters, on expression and function of PCFT in MCs. Primary MCs, isolated from neonatal mouse retinas, were treated with MMF, and PCFT function was monitored by measuring uptake of radiolabeled methyltetrahydrofolate (MTF) at pH 5.5. Dose-response and time-course analyses were performed to identify optimal conditions for maximal effect. The influence of MMF treatment on kinetic parameters of PCFT was studied, and PCFT expression was analyzed at the mRNA and protein level. MTF uptake in MCs decreased by ̃50% following 18 h treatment with 1 mM MMF. This effect was specific to fumaric acid esters. MMF treatment decreased the maximal velocity of the transporter without altering substrate affinity. The decrease in PCFT function following MMF treatment was accompanied by attenuated PCFT expression. This is the first report that an antipsoriatic compound can regulate folate transport in MCs and may have potential for the treatment of reactive gliosis in retinal disease.
KW - Folic acid
KW - Fumaric acid esters
KW - Mouse
KW - Müller cell gliosis
KW - Vitamin transport
UR - http://www.scopus.com/inward/record.url?scp=84856231188&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84856231188&partnerID=8YFLogxK
U2 - 10.1002/glia.22266
DO - 10.1002/glia.22266
M3 - Article
C2 - 22072423
AN - SCOPUS:84856231188
VL - 60
SP - 333
EP - 342
JO - GLIA
JF - GLIA
SN - 0894-1491
IS - 3
ER -