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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.


J Neurochem. 2012 Oct 4;


Authors: Durk MR, Chan GN, Campos CR, Peart JC, Chow EC, Lee E, Cannon RE, Bendayan R, Miller DS, Sandy Pang K


Abstract

MDR1/P-gp induction 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, 1α,25-dihydroxyvitamin D(3) [1,25(OH)(2) D(3) ] for 4 h increased P-gp protein expression (4-fold). 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 RBE4 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 (hAβ(42) ). In hCMEC/D3 cells, a three day exposure to 100 nM 1,25(OH)(2) D(3) increased MDR1 mRNA expression (40%) and P-gp protein (3-fold); cellular accumulation of R6G and hΑβ(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 hAβ(42) , a plaque-forming precursor in Alzheimer's disease. © 2012 International Society for Neurochemistry, J. Neurochem. (2012) 10.1111/jnc.12041.

PMID: 23035695 [PubMed - as supplied by publisher]