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1α,25‐Dihydroxyvitamin D 3 ‐liganded vitamin D receptor increases expression and transport activity of P‐glycoprotein in isolated rat brain capillaries and human and rat brain microvessel endothelial cells
Author(s) -
Durk Matthew R.,
Chan Gary N.Y.,
Campos Christopher R.,
Peart John C.,
Chow Edwin C. Y.,
Lee Eason,
Can Ronald E.,
Bendayan Reina,
Miller David S.,
Pang K. Sandy
Publication year - 2012
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12041
Subject(s) - calcitriol receptor , microvessel , p glycoprotein , receptor , microbiology and biotechnology , biology , endocrinology , medicine , chemistry , biochemistry , multiple drug resistance , immunology , immunohistochemistry , antibiotics
Induction of the multidrug resistance protein 1 (MDR1)/P‐glycoprotein (P‐gp) by the vitamin D receptor ( VDR ) was investigated in isolated rat brain capillaries and rat ( RBE 4) and human ( hCMEC /D3) brain microvessel endothelial cell lines. Incubation of isolated rat brain capillaries with 10 nM of the VDR ligand, 1α,25‐dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ] for 4 h increased P‐gp protein expression fourfold. Incubation with 1,25(OH) 2 D 3 for 4 or 24 h increased P‐gp transport activity (specific luminal accumulation of NBD ‐ CSA , the fluorescent P‐gp substrate) by 25–30%. In RBE 4 cells, Mdr1b mRNA was induced in a concentration‐dependent manner by exposure to 1,25(OH) 2 D 3 . Concomitantly, P‐gp protein expression increased 2.5‐fold and was accompanied by a 20–35% reduction in cellular accumulation of the P‐gp substrates, rhodamine 6G (R6G), and HiLyte Fluor 488‐labeled human amyloid beta 1‐42 ( hA β 42 ). In hCMEC /D3 cells, a 3 day exposure to 100 nM 1,25(OH) 2 D 3 increased MDR 1 mRNA expression (40%) and P‐gp protein (threefold); cellular accumulation of R6G and hAβ 42 was reduced by 30%. Thus, VDR activation up‐regulates Mdr1/ MDR 1 and P‐gp protein in isolated rat brain capillaries and rodent and human brain microvascular endothelia, implicating a role for VDR in increasing the brain clearance of P‐gp substrates, including hAβ 42 , a plaque‐forming precursor in Alzheimer's disease.