RGD Reference Report - Functional induction of P-glycoprotein in the blood-brain barrier of streptozotocin-induced diabetic rats: evidence for the involvement of nuclear factor-kappaB, a nitrosative stress-sensitive transcription factor, in the regulation. - Rat Genome Database

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Functional induction of P-glycoprotein in the blood-brain barrier of streptozotocin-induced diabetic rats: evidence for the involvement of nuclear factor-kappaB, a nitrosative stress-sensitive transcription factor, in the regulation.

Authors: Maeng, HJ  Kim, MH  Jin, HE  Shin, SM  Tsuruo, T  Kim, SG  Kim, DD  Shim, CK  Chung, SJ 
Citation: Maeng HJ, etal., Drug Metab Dispos. 2007 Nov;35(11):1996-2005. Epub 2007 Jul 30.
RGD ID: 2312730
Pubmed: PMID:17664251   (View Abstract at PubMed)
DOI: DOI:10.1124/dmd.107.015800   (Journal Full-text)

The objective of this study was to investigate the transport kinetics of cyclosporin A, a well known substrate for P-glycoprotein (P-gp), across the blood-brain barrier (BBB), and the expression of the transporter in the brain of streptozotocin-induced diabetic rats. The in vivo transport clearance of cyclosporin A was significantly reduced in diabetic rats compared with that in the control. The decreased transport was associated with the increased level of mRNA and the protein for P-glycoprotein in the rat brain. The functional activity of the efflux transporter in mouse brain capillary endothelial (MBEC4) cells, an in vitro model of the BBB, was also stimulated when slow nitric oxide (NO)-releasing donors were present, whereas the stimulation was absent in the case of rapid NO-releasing donors (e.g., S-nitroso-N-acetyl-dl-penicillamine and diethylenetriamine). The stimulatory effect was highest for sodium nitroprusside (SNP) and the functional induction associated with the increased mRNA and protein level of the transporter. The pretreatment of the cell with SNP along with ascorbate, methylene blue, or superoxide dismutase attenuated the induction of function and expression for P-glycoprotein, suggesting that the reaction product between superoxide and NO is involved in the induction of function and expression. The level of nuclear translocation of nuclear factor-kappaB (NF-kappaB) and DNA binding activity of nuclear extracts to the NF-kappaB consensus oligonucleotide was increased in MBEC4 cells pretreated with SNP. Taken together, these observations suggest that nitrosative stress leads to the up-regulation of the message for the efflux transporter and, ultimately, to the enhanced function, probably via a NF-kappaB-dependent mechanism.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Experimental Diabetes Mellitus  ISOAbcb1a (Rattus norvegicus)2312730; 2312730mRNA:increased expression:brainRGD 
Experimental Diabetes Mellitus  ISOAbcc2 (Rattus norvegicus)2312730; 2312730mRNA: increased expression: brainRGD 
Experimental Diabetes Mellitus  IEP 2312730; 2312730mRNA:increased expression:brainRGD 
Experimental Diabetes Mellitus  ISOAbcb1b (Rattus norvegicus)2312730mRNA:increased expression:brainRGD 
Experimental Diabetes Mellitus  IEP 2312730mRNA: increased expression: brainRGD 

Objects Annotated

Genes (Rattus norvegicus)
Abcb1a  (ATP binding cassette subfamily B member 1A)
Abcb1b  (ATP-binding cassette, sub-family B member 1B)
Abcc2  (ATP binding cassette subfamily C member 2)

Genes (Mus musculus)
Abcb1a  (ATP-binding cassette, sub-family B member 1A)
Abcb1b  (ATP-binding cassette, sub-family B member 1B)
Abcc2  (ATP-binding cassette, sub-family member 2)

Genes (Homo sapiens)
ABCB1  (ATP binding cassette subfamily B member 1)
ABCC2  (ATP binding cassette subfamily C member 2)


Additional Information