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Renal efflux transporter expression in pregnant mice with Type I diabetes
Lindsay L Yacovino1, Lauren M Aleksunes
1Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, 170 Frelinghuysen Rd, Piscataway, NJ 08854, USA.
Abstract:
Prior research suggests that sex hormones and metabolic changes, such as obesity and hyperglycemia, can alter renal transporter expression in rodents. The purpose of this study was to characterize the expression of kidney efflux transporters and regulatory transcription factors in response to Type I diabetes and pregnancy. Female C57BL/6 mice were treated with multiple low doses of streptozotocin (STZ) to induce hyperglycemia and then mated with normoglycemic male mice. Transporter mRNA and protein expression were quantified in kidneys from vehicle- and STZ-treated non-pregnant and pregnant mice on gestation day 14. Pregnancy decreased the expression of Mdr1b, Mrp4, and 5 proteins and increased the mRNA and protein expression of Mrp3 by 50-60%. STZ treatment elevated Mrp1, 2, 4, and 5 and reduced Mrp3, 6, and Mdr1b mRNA and/or protein in non-pregnant mice. Pregnancy had little effect on STZ-mediated changes in renal efflux transporter expression. Transcriptional profiles of Hnf1α, PXR, AhR, and Nrf2 were altered in patterns similar to some efflux transporters suggesting potential involvement in their regulation. Taken together, these results suggest that renal drug efflux transporters and regulatory signaling pathways are altered by endocrine and metabolic changes that occur during pregnancy and Type I diabetes.
Insights
Pregnancy and Type I diabetes alter kidney efflux transporters, impacting drug transport. These changes involve key regulatory factors, suggesting altered drug metabolism during these conditions.
Area of Science:
- Pharmacology
- Nephrology
- Endocrinology
Background:
- Sex hormones and metabolic changes influence renal transporter expression.
- Obesity and hyperglycemia are known to alter kidney function.
- Understanding these alterations is crucial for drug efficacy and safety.
Purpose of the Study:
- To characterize kidney efflux transporter and transcription factor expression.
- To investigate changes in response to Type I diabetes and pregnancy.
- To identify potential regulatory mechanisms involved.
Main Methods:
- Female mice were induced with hyperglycemia using streptozotocin (STZ).
- Mice were studied during pregnancy and non-pregnant states.
- Kidney mRNA and protein expression of transporters and transcription factors were quantified.
Main Results:
- Pregnancy altered expression of Mdr1b, Mrp3, Mrp4, and Mrp5.
- STZ treatment significantly changed expression of Mrp1, Mrp2, Mrp3, Mrp4, Mrp5, Mrp6, and Mdr1b.
- Pregnancy minimally affected STZ-induced changes; transcription factors Hnf1α, PXR, AhR, and Nrf2 showed altered profiles.
Conclusions:
- Renal drug efflux transporters are altered by Type I diabetes and pregnancy.
- Regulatory signaling pathways are implicated in these transporter alterations.
- These findings suggest potential changes in drug disposition during pregnancy and diabetes.
