Placental transferrin receptor 1, fetal tissue iron, and renal development in different etiologies of intrauterine growth restriction.

摘要

Intrauterine growth restriction (IUGR) from several causes disrupts iron transport and impairs renal function. Transferrin receptor (TfR1) is the major cell-surface protein transporting iron on the villus side of the placenta. TfR1 expression is controlled by iron regulatory proteins (IRP), which are partly mediated by nitric oxide (NO). NO is biosynthesized by L-arginine via several nitric oxide synthases (NOS), including endothelial NOS (eNOS), found in most tissues. Limited data show that estrogen modulates iron homeostasis possibly through increased expression of eNOS, thereby enhancing TfR1, and ultimately facilitating cellular iron uptake. We hypothesize that three different IUGR models representing the most common clinical causes of IUGR including multifetal gestation, aromatase inhibition, and gestational iron deficiency (ID) will result in altered placental TfR1 expression in association with reduced eNOS along with impaired renal development, which ultimately lead to hypertension. In the first study we utilized an ovine surgical uterine space restriction (USR) model, combined with multifetal gestation, to test the extremes of uterine and placental adaptation on placental TfR1, eNOS, and regulation of fetal iron status. This study demonstrated that placental eNOS appeared to be involved in the regulation of placental TfR1 expression. Fetal iron was regulated in an organ-specific fashion with similar liver iron. Also IUGR fetuses adapted to USR by delivering more iron via the blood and accretion by the kidney. In the following study we employed the same USR model to further investigate fetal renal development and metabolism. We reported that major renal adaptations were observed in USR fetuses including immature renal development and endocrine function, along with evidence for impaired renal excretory function. We also concluded in the study that the relatively greater renal iron observed might be for ongoing cell proliferation during nephrogenesis. In the third study, an ovine model of aromatase inhibition to reduce endogenous placental estrogen production was employed to further examine the relationship between placental TfR1 and eNOS as well as fetal renal development and metabolism in IUGR. Aromatase inhibition significantly reduced placental TfR1 in a non-NO mediated fashion and impaired renal development with renal histological similarities to the USR model. This study demonstrated a role of estrogen in controlling iron metabolism during pregnancy. In the final study, a rat gestational ID model was used to examine the impact of ID on immediate postnatal rat renal development. We report herein that although placental TfR1 was higher in gestational ID, it was not related to placental eNOS. Gestational ID also impaired renal development similar to the ovine models of USR and aromatase inhibition with observations of renal programming with lower blood pressure and an eventual rise in adulthood. Collectively, these studies enhance the understanding of placental TfR1 regulation in compromised pregnancies in association with fetal and postnatal iron status. More importantly, this dissertation provides strong evidence for the role iron plays in renal development and the consequences of IUGR on renal adaptation particularly in the programming for hypertension in adulthood.