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Maternal malnutrition and placental insufficiency induce global downregulation of gene expression in fetal kidneys

Published online by Cambridge University Press:  10 December 2010

O. Denisenko*
Affiliation:
Department of Medicine, University of Washington, Seattle, WA, USA
B. Lin
Affiliation:
Division of Nephrology, Oregon Health & Science University, Portland, OR, USA Research Service, Portland VA Medical Center, Portland, OR, USA
S. Louey
Affiliation:
Heart Research Center, Oregon Health & Science University, Portland, OR, USA Division of Cardiovascular Medicine, Oregon Health & Science University, Portland, OR, USA
K. Thornburg
Affiliation:
Heart Research Center, Oregon Health & Science University, Portland, OR, USA Division of Cardiovascular Medicine, Oregon Health & Science University, Portland, OR, USA
K. Bomsztyk
Affiliation:
Department of Medicine, University of Washington, Seattle, WA, USA
S. Bagby
Affiliation:
Heart Research Center, Oregon Health & Science University, Portland, OR, USA Division of Nephrology, Oregon Health & Science University, Portland, OR, USA Research Service, Portland VA Medical Center, Portland, OR, USA
*
*Address for correspondence: O. Denisenko, Department of Medicine, University of Washington, 815 Mercer Street, Room 244, Seattle, WA 98109, USA. (Email odenis@uw.edu)

Abstract

Malnutrition during pregnancy causes intrauterine growth restriction and long-term changes in the offspring's physiology and metabolism. To explore molecular mechanisms by which the intrauterine environment conveys programming in fetal kidneys, an organ known to undergo substantial changes in many animal models of late gestational undernutrition, we used a microswine model of maternal protein restriction (MPR) in which sows were exposed to isocaloric low protein (LP) diet during late gestation/early lactation to encompass the bulk of nephrogenesis. To define general v. model-specific effects, we also used a sheep model of placental insufficiency. In kidneys from near-term fetal and neonatal microswine LP offspring, per cell levels of total RNA, poly(A)+ mRNA and transcripts of several randomly chosen housekeeping genes were significantly reduced compared to controls. Microarray analysis revealed only a few MPR-resistant genes that escape such downregulation. The ratio of histone modifications H3K4m3/H3K9m3 (active/silenced) was reduced at promoters of downregulated but not MPR-resistant genes suggesting that transcriptional suppression is the point of control. In juvenile offspring, on a normal diet from weaning, cellular RNA levels and histone mark patterns were recovered to near control levels, indicating that global repression of transcription is dependent on ongoing MPR. Importantly, cellular RNA content was also reduced in ovine fetal kidneys during placental insufficiency. These studies show that global repression of transcription may be a universal consequence of a poor intrauterine environment that contributes to fetal restriction.

Type
Original Articles
Copyright
Copyright © Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2010

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