Increase in P-glycoprotein accompanied by activation of protein kinase Cα and NF-κB p65 in the livers of rats with streptozotocin-induced diabetes

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 PKC alpha and the transcription factor NF-kappa B, we investigated the expression levels of Mdr1a, Mdr1b, Mdr2, Mrp2, Bcrp, Bsep, Oct1, Oat2, and Oat3 transporters, PKC alpha, I kappa B, and NF-kappa B in the liver of Fats 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 PKC alpha was not affected, translocation of PKC alpha to the microsomal fraction was detected. NF-kappa B p65, I kappa B alpha and I kappa B beta mRNA levels were increased as was the level of nuclear NF-kappa B p65. From these findings, it was suggested that STZ-induced hyperglycemia caused the upregulation of Mdr1b P-gp expression through the activation of PKC alpha and NF-kappa B. (c) 2008 Elsevier B.V. All rights reserved.