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

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, kidneypredominant 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 ␣ 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)-1␤ 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.

Regulatory Pathways for ATP-binding Cassette Transport Proteins in Kidney Proximal Tubules

“…This was confirmed for P-gp in rat livers, but not in kidneys, and after testosterone treatment P-gp levels in females reduced to male rat liver levels (40). The same study showed a similar effect on Mrp2 in rat livers, whereas Abcc2 gene expression levels were comparable in female and male kidney (39). For Mrp4, female predominant appearance is observed in murine kidney and liver (41).…”

“…Abcb1b, but not Abcb1a, gene expression is somewhat higher in females than in male mice kidneys (39). This was confirmed for P-gp in rat livers, but not in kidneys, and after testosterone treatment P-gp levels in females reduced to male rat liver levels (40).…”

Expression Profiles of Metabolic Enzymes and Drug Transporters in the Liver and along the Intestine of Beagle Dogs

“…In this work, canine ABCC1 expression correlated with that in human, with lower levels in the liver than in the intestine (Bleasby et al, 2006); however, in contrast to the other studied genes, the mRNA levels increased toward the large intestine (2.4-fold higher in the colon than in the jejunum). A similar gene expression trend along the gut was also observed in rats (Lu and Klaassen, 2008).…”

Gene expression profiling of ABC transporters in dermal fibroblasts of pseudoxanthoma elasticum patients identifies new candidates involved in PXE pathogenesis

“…These results are consistent with a previous study reporting gender differences in abcc2/mrp2 mRNA and protein expression in a mouse model for chronic kidney disease. 49 Abcc2/mrp2, abcc3/mrp3 and abcc4/mrp4 expression in mice were also reported to be induced in the context of oxidative stress. 50 Mild chronic oxidative stress might be involved in PXE manifestation.…”