Gender Differences in mRNA Expression of ATP-Binding Cassette Efflux and Bile Acid Transporters in Kidney, Liver, and Intestine of 5/6 Nephrectomized Rats

Abstract

ATP-binding cassette (ABC) transporters including multidrug resistance proteins (Mdr), multidrug resistance-associated proteins (Mrp), and breast cancer resistance protein (Bcrp/Abcg2) play major roles in tissue defense. Abcg5/g8 is essential in cholesterol efflux. The present study was aimed at elucidating alteration in expression of these transporters and bile-acid transporters during chronic kidney disease (CKD) and underlying molecular mechanisms. Seven weeks after 5/6 nephrectomy (Nx), mRNA expression of 16 aforementioned transporters in kidney, liver, jejunum, and large intestine of male and female Nx rats was quantified with the branched DNA signal amplification assay. In Nx males, intestinal expression of all the transporters remained unchanged; hepatic expression of most transporters was not altered, except increases in Mdr1a, Mrp3, and Abcg8. In male remnant kidneys, kidney-predominant transporter Abcg2 decreased and correlated with CKD severity, whereas Mdr1b, Mrp3, and ileal bile-acid transporter increased and correlated with CKD severity. Such changes were largely absent in Nx females. Renal alterations of these transporters correlated with increases of cytokines and/or decreases of nuclear receptors such as estrogen receptor alpha and glucocorticoid receptor. Renal protein expression of Mrp2 increased, whereas that of Mrp4 remained unchanged in both genders of Nx rats. Treatment of rat proximal tubule NRK-52E cells with interleukin (IL)-1beta and IL-6 increased Mrp3 mRNA expression. In conclusion, during CKD, renal expression of many ABC transporters was altered at the transcriptional level, whereas hepatic mRNA expression of most ABC transporters remained unchanged. Down-regulation of steroid hormone receptors and increase of inflammatory cytokines may contribute to alteration of transporter gene expression in kidney during CKD.