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Am J Physiol Regul Integr Comp Physiol (July 7, 2005). doi:10.1152/ajpregu.00211.2005
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Submitted on March 25, 2005
Accepted on June 29, 2005

Uteroplacental Insufficiency Alters Hepatic Expression, Phosphorylation and Activity of the Glucocorticoid Receptor in Fetal IUGR Rats

Mariana Baserga1*, Merica Hale1, Robert A McKnight1, Xing Yu1, Christopher W Callaway1, and Robert H Lane1

1 Department of Pediatrics, Division of Neonatology, University of Utah School of Medicine, Salt Lake City, UT, USA

* To whom correspondence should be addressed. E-mail: mariana.baserga{at}hsc.utah.edu.

Uteroplacental insufficiency (UPI) induces persistent changes in hepatic gene expression secondary to altered chromatin dynamics in the rat IUGR liver. The glucocorticoid receptor (GR) is a transcription factor that when activated can induce changes in chromatin structure. To begin the process of identifying pathways by which IUGR affects chromatin structure, we hypothesized that UPI in the rat induces a significant increase in endogenous glucocorticoids (corticosterone) and increases GR expression and activation. To prove our hypothesis, we induced IUGR through bilateral uterine artery ligation of the pregnant rat. At D1, UPI significantly increased corticosterone levels and was associated with increased total GR mRNA and protein levels in the liver, as well as increased hepatic phosphorylation of GR serine 211. Moreover, cyclin-dependent kinase 2 (cyclinA/CDK2) protein levels, which selectively phosphorylate GR serine 211, were also significantly increased. To assess activity of the GR, we measured protein levels of the transcription factor p53, whose levels are downregulated, at least in part, by active GR. In this study, UPI decreased p53 protein and its downstream target, Bax mRNA levels. We conclude that UPI in rats affects GR expression, and activity in the liver. We speculate that these alterations early in life may contribute to the changes in chromatin structure and gene expression previously described in the IUGR liver.




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