Vitamin D deficiency is common in pregnant women and has been associated with pregnancy complications such as recurrent miscarriages, pre-term delivery and pre-eclampsia. However, the endogenous and exogenous factors that regulate the levels of active vitamin D and its biological effects at target tissues during pregnancy remain largely uncharacterized. Recently, we discovered that healthy pregnancies, as shown in Lewis and Sprague-Dawley rats, are associated with increased levels of active vitamin D throughout pregnancy. Vitamin D sufficiency is associated with maternal kidney-specific decreases in the protein levels of the vitamin D receptor (VDR) and the vitamin D inactivating enzyme CYP24a1. In contrast, Brown Norway rats experience a pregnancy-induced deficiency of the active metabolite of vitamin D associated with maternal renal upregulation of VDR and CYP24a1. Therefore, we hypothesize that maternal renal VDR is down-regulated via proteasomal degradation in normal pregnancies leading to decreased VDR-dependent activation of key genes such as CYP24a1.
Our specific aims are: 1) Determine the role of maternal renal VDR expression changes in VD status and pregnancy outcomes, and 2) Characterize the mechanisms of maternal renal VDR regulation during pregnancy. We will alter maternal renal VDR expression using intraarterial injections of adenovirus containing full length VDR (to increase VDR levels) or VDR siRNA (to decrease VDR levels). We will study plasma levels of VD metabolites, pregnancy outcomes, uterine artery remodeling and maternal blood pressure and presence of proteinuria. We will perform VDR co-immunoprecipitation assays followed by proteomic analysis to discover novel VDR protein-protein interactions in non-pregnant and pregnant kidneys. Finally, we will perform cDNA microarrays on maternal kidneys from Brown Norway and Sprague-Dawley rats to identify differentially expressed genes. We will then characterize the regulation of these genes in non-pregnant kidneys and pregnant kidneys treated with adenoviruses to identify VDR-dependent genes. The results of these aims will further our knowledge on VD status and function during normal and complicated pregnancies.
Vitamin D deficiency during pregnancy is highly prevalent and has been associated with pregnancy and neonatal disease. This proposal will study the maternal renal vitamin D receptor regulation and its role in determining vitamin D sufficiency during pregnancy.