Vitamin D deficiency has been associated with pregnancy complications such as preeclampsia, gestational diabetes, and recurrent miscarriage. Therefore, we hypothesized differences in vitamin D status between healthy [Sprague-Dawley (SD) and Lewis (LW)] and complicated [Brown Norway (BN)] rat pregnancies. In SD, LW, and BN rats, we analyzed the maternal plasma levels of the vitamin D metabolites 25-OH-D and 1,25-(OH)2-D at prepregnancy, pregnancy, and postpartum. Analysis of the active metabolite 1,25-(OH)2-D showed a twofold increase in pregnant SD and LW rats but a nearly 10-fold decrease in pregnant BN rats compared with nonpregnant controls. BN rats had a pregnancy-dependent upregulation of CYP24a1 expression, a key enzyme that inactivates vitamin D metabolites. In contrast, the maternal renal expression of CYP24a1 in SD and LW rats remained constant throughout pregnancy. Analysis of the vitamin D receptor (VDR) indicated that LW and SD but not BN rats experience a pregnancy-induced 10-fold decrease in maternal renal VDR protein levels. Further analysis of bisulfite-converted and genomic DNA indicated that the observed differences in maternal renal regulation of CYP24a1 during pregnancy and lactation are not due to differences in CYP24a1 promoter methylation or single-nucleotide polymorphisms. Finally, supplementation with 1,25-(OH)2-D significantly improved the reproductive phenotype of BN rats by increasing litter size and maternal-fetal weight outcomes. We conclude that BN rats represent a novel animal model of pregnancy-specific vitamin D deficiency that is linked to pregnancy complications. Vitamin D deficiency in BN rats correlates with maternal renal CYP24a1 upregulation followed by CYP27b1 upregulation.
Keywords: CYP24a1; calcitriol; kidney; metabolism; placenta.