Journal
JOURNAL OF NEUROCHEMISTRY
Volume 123, Issue 6, Pages 944-953Publisher
WILEY
DOI: 10.1111/jnc.12041
Keywords
1a; 25-dihydroxyvitamin D3 and vitamin D receptor; amyloid beta; blood brain barrier; P-glycoprotein
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Funding
- Canadian Institutes of Health Research (CIHR)
- Intramural Research Program of the National Institute of Environmental Health Sciences, NIH
- CIHR Strategic Training Grant in Biological Therapeutics (CIHR)
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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 (RBE4) and human (hCMEC/D3) brain microvessel endothelial cell lines. Incubation of isolated rat brain capillaries with 10 nM of the VDR ligand, 1a,25-dihydroxyvitamin D3 [1,25(OH)2D3] for 4 h increased P-gp protein expression fourfold. Incubation with 1,25(OH)2D3 for 4 or 24 h increased P-gp transport activity (specific luminal accumulation of NBD-CSA, the fluorescent P-gp substrate) by 2530%. In RBE4 cells, Mdr1b mRNA was induced in a concentration-dependent manner by exposure to 1,25(OH)2D3. Concomitantly, P-gp protein expression increased 2.5-fold and was accompanied by a 2035% reduction in cellular accumulation of the P-gp substrates, rhodamine 6G (R6G), and HiLyte Fluor 488-labeled human amyloid beta 1-42 (hA beta 42). In hCMEC/D3 cells, a 3 day exposure to 100 nM 1,25(OH)2D3 increased MDR1 mRNA expression (40%) and P-gp protein (threefold); cellular accumulation of R6G and hA beta 42 was reduced by 30%. Thus, VDR activation up-regulates Mdr1/MDR1 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 hA beta 42, a plaque-forming precursor in Alzheimer's disease.
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