title: Increase in P-glycoprotein accompanied by activation of protein kinase Calpha and NF-kappaB p65 in the livers of rats with streptozotocin-induced diabetes.
abstract: It is known that protein kinase C (PKC) signal transduction is enhanced in a diabetic state, and that PKC activator phorbol esters increase the gene expression of MDR1 in human tumor cells. To clarify the expression of the liver transporters under diabetic conditions and the roles of PKCalpha and the transcription factor NF-kappaB, we investigated the expression levels of Mdr1a, Mdr1b, Mdr2, Mrp2, Bcrp, Bsep, Oct1, Oat2, and Oat3 transporters, PKCalpha, IkappaB, and NF-kappaB in the liver of rats with STZ-induced hyperglycemia. A selective increase in the gene expression of Mdr1b was detected by RT-PCR. Western blotting with C219 antibody revealed an increase in P-glycoprotein. Although the mRNA level of PKCalpha was not affected, translocation of PKCalpha to the microsomal fraction was detected. NF-kappaB p65, IkappaBalpha and IkappaBbeta mRNA levels were increased as was the level of nuclear NF-kappaB p65. From these findings, it was suggested that STZ-induced hyperglycemia caused the upregulation of Mdr1b P-gp expression through the activation of PKCalpha and NF-kappaB.
authors.affiliation: Department of Medical Technology, Nagoya University School of Health Sciences, 1-1-20 Daikominami, Nagoya 461-8673, Japan.
authors.forename: Natsumi
authors.initials: N
authors.lastname: Kameyama
authors.forename: Sakiko
authors.initials: S
authors.lastname: Arisawa
authors.forename: Jun
authors.initials: J
authors.lastname: Ueyama
authors.forename: Satomi
authors.initials: S
authors.lastname: Kagota
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Shinozuka
authors.forename: Ai
authors.initials: A
authors.lastname: Hattori
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Tatsumi
authors.forename: Hisao
authors.initials: H
authors.lastname: Hayashi
authors.forename: Kenji
authors.initials: K
authors.lastname: Takagi
authors.forename: Shinya
authors.initials: S
authors.lastname: Wakusawa
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose; D001835:Body Weight; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology*; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000201:enzymology*; D008297:Male; D009929:Organ Size; D010641:Phenotype; D051571:Protein Kinase C-alpha / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001786:Blood Glucose; D020672:I-kappa B Proteins; D051996:Transcription Factor RelA; D013311:Streptozocin; D051571:Protein Kinase C-alpha