TitleCharacterization of renal transporter expression in mice
during pregnancy, lactation, and type I diabetes
NameYacovino, Lindsay Lee (author), Reuhl, Kenneth (chair), Aleksunes, Lauren (internal member), Gallo, Michael (internal member), Thomas, Paul (internal member), Rutgers University, Graduate School - New Brunswick,
Renal tubular transport,
Mice as laboratory animals ,
DescriptionRenal transporters regulate the reabsorption and secretion of nutrients, drugs, and toxicants. Modification of their expression and/or activity can alter renal clearance, affecting drug efficacy and toxicity. Prior work has suggested that sex hormones and metabolic changes, like diabetes and obesity, alter renal transporter expression in rodents. The purpose of this thesis was to characterize the mRNA and protein expression of renal uptake and efflux transporters and potential regulatory transcription factors in response to gestation, lactation, and type I diabetes in female C57BL/6 mice. In a time-course study, kidney transporter mRNA and protein expression were evaluated using qPCR, western blot, and immunofluorescence staining on gestation days (GD) 7, 11, 14, and 17 and postnatal days (PD) 1, 15, and 30. Pregnancy caused marked down-regulation of apical efflux transporters Mdr1b, Mrp2, Mrp4, and Mate1 and up-regulation of basolateral efflux transporter Mrp3. Mdr1b and Mrp4 mRNA decreased early in pregnancy and remained low throughout lactation whereas Mrp1, Mrp2, and Mate1 mRNA expression did not begin to decline until mid-gestation. A marked increase in Mrp3 mRNA and protein was observed at mid-gestation. Western blot and immunofluorescence staining confirmed reduced protein expression of Mrp2 and Mrp4 and elevated Mrp3 levels in pregnant mice. For the diabetic pregnancy study, female C57BL/6 mice were treated repeatedly with intraperitoneal doses of vehicle or streptozotocin (STZ) to induce type I diabetes. After two weeks of hyperglycemia, STZ-and vehicle-treated control mice were mated overnight and tissues collected 14 days later. Both efflux and uptake renal transporters were differentially regulated in response to STZ treatment. STZ decreased mRNA expression of Oat2, Oat5, and Mrp3 and elevated levels of Oatp2b1, Oatp4c1, Pept1, Mrp2, Mrp4, and Mrp5. Pregnancy had little effect on STZ-mediated down-regulation of Oat2 and Oat5 mRNA, but did prevent up-regulation of Oatp4c1 and Mrp4 mRNA. In both the time-course and diabetic pregnancy studies, mRNA profiling revealed transcription factors (AhR, PXR, HNF1α, PPARα and Nrf2) that might participate in regulating renal transporter expression. Taken together, these results suggest that renal drug transport and regulatory signaling pathways are altered by endocrine and metabolic changes that occur during pregnancy and diabetes.
NoteIncludes bibliographical references
Noteby Lindsay Lee Yacovino
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.