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Human epidemiological data associating birth weight with adult disease suggest that organogenesis is "programmed" by maternal diet. In rats, protein restriction in pregnancy produces offspring with fewer renal glomeruli and higher systemic blood pressures than controls. We tested the hypothesis that maternal diet alters gene expression in the metanephros, the precursor of the definitive mammalian kidney. We demonstrated that maternal low-protein diet initiated when pregnancy starts and maintained to embryonic day 13, when the metanephros consists of mesenchyme surrounding a once-branched ureteric bud, is sufficient to significantly reduce glomerular numbers in offspring by about 20%. As assessed by representational difference analyses and real-time quantitative polymerase chain reactions, low-protein diet modulated gene expression in embryonic day 13 metanephroi. In particular, levels of prox-1, the ortholog of Drosophila transcription factor prospero, and cofilin-1, a regulator of the actin cytoskeleton, were reduced. During normal metanephrogenesis, prox-1 protein was first detected in mesenchymal cells around the ureteric tree and thereafter in nascent nephron epithelia, whereas cofilin-1 immunolocalized to bud derivatives and condensing mesenchyme. Previously, we reported that low-protein diets increased mesenchymal apoptosis cells when metanephrogenesis began and thereafter reduced numbers of precursor cells. Collectively, these studies prove that the maternal diet programs the embryonic kidney, altering cell turnover and gene expression at a time when nephrons and glomeruli have yet to form. The human implication is that the maternal diet ingested between conception and 5- 6-wk gestation contributes to the variation in glomerular numbers that are known to occur between healthy and hypertensive populations.

Original publication

DOI

10.1152/physiolgenomics.00167.2004

Type

Journal article

Journal

Physiol Genomics

Publication Date

16/06/2005

Volume

22

Pages

48 - 56

Keywords

Animals, Cofilin 1, Diet, Diet, Protein-Restricted, Female, Gene Expression Regulation, Developmental, Homeodomain Proteins, Immunohistochemistry, Kidney, Kidney Glomerulus, Maternal Nutritional Physiological Phenomena, Pregnancy, Protein Transport, Proto-Oncogene Proteins c-bcl-2, Rats, Rats, Wistar, Reverse Transcriptase Polymerase Chain Reaction, Tumor Suppressor Proteins, bcl-2-Associated X Protein