Pregnancy increases the urinary excretion of chemicals in women and rodents. mid to late gestation but returned to control levels by postnatal day 15. CX-5461 In contrast, Mrp3 mRNA and protein increased 225% and 31%, respectively, at gestational day 14. Coordinated down-regulation of brush border transporters Mate1, Mrp2, and Mrp4 and up-regulation of the basolateral Mrp3 transporter would reduce chemical secretion into urine. Introduction Pregnancy-induced hormonal and hemodynamic changes significantly alter renal function. In humans and rodents, increases in cardiac output and renal vasodilation enlarge the size of the kidneys, elevate renal plasma flow by 50C85%, and increase the rate of glomerular filtration by 40C65% (Chapman et al., 1998; Conrad, 2004; Maynard and Thadhani, 2009; Cornelis et al., 2011). Clinically, pregnant women exhibit proteinuria, glucosuria, and aminoaciduria, which have been attributed to alterations in renal function (Davison and Dunlop, 1980; Cornelis et al., 2011). Together, hyperfiltration and increased blood flow to the kidneys alter maternal pharmacokinetics by elevating the renal clearance of chemicals during pregnancy. Renal transporters are membrane-spanning proteins that play a critical role in facilitating the movement of toxins and drugs into the urine via secretion and into the blood via reabsorption. To enable these processes, transporters are prominently localized on both the apical (brush border) and basolateral membranes of proximal tubule epithelial cells. Transporters expressed within the kidneys are members of one of the two superfamilies: the solute carrier (SLC) and ATP-binding cassette (ABC) families. Efflux transporters that extrude chemicals from cells are members of both the ABC and the SLC families and include the multidrug resistanceCassociated proteins (Mrps), multidrug resistance proteins (Mdrs), breast cancer resistance protein (Bcrp), and multidrug and toxin extrusion proteins (Mates) (reviewed in Klaassen and Aleksunes, 2010). Recent studies have begun to explore transporter regulation in the kidneys during pregnancy and the subsequent postpartum period. In one study, expression of renal Mdr1b mRNA in mice decreased between mid and late gestation, with little to no change at the protein level (Zhang et al., 2008). In addition, expression of Bcrp in kidneys of mice was generally unchanged throughout pregnancy, with an increase CX-5461 in mRNA and protein only during mid-gestation (Wang et al., 2006). Despite these prior investigations, there are no studies CX-5461 that have systematically investigated the coordinated expression of apical and CX-5461 basolateral renal transporters in pregnant rodents during different periods of pregnancy and lactation. Studies investigating the influence of pregnancy on renal clearance have focused predominantly on overall maternal pharmacokinetic parameters. Clinically, the urinary clearance of drugs, such as ceftazidime, atenolol, and amoxicillin, is often elevated during pregnancy (Hebert et al., 2005; Nathorst-Boos et al., 1995; Andrew et al., 2007). The renal secretion and urinary clearance of the cardiac glycoside digoxin ENOX1 has also been shown to increase in a study of 13 pregnant patients (Hebert et al., 2008). Because digoxin is a substrate of the MDR1 transporter, the study by Hebert et al. (2008) indirectly suggested that elevated renal CX-5461 MDR1 activity may participate in the increased tubular secretion and clearance of digoxin during pregnancy (Kawahara et al., 1999; Hebert et al., 2008). Because of the enhanced urinary clearance of chemicals in humans and rodents during pregnancy, we hypothesized that expression of efflux transporters would favor renal secretion and limit reabsorption. Therefore, the purpose of the current study was to quantify the mRNA and protein expression of efflux transporters in the kidneys of mice during pregnancy and lactation. Mice were selected for this analysis because of their increasing use in developmental toxicology studies. The results obtained from this study will provide new insight into the potential contribution of renal transporters to.