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1 Nephro-Urology, Institute of Child Health, University College, London, United Kingdom
2 Molecular Medicine, Institute of Child Health, University College, London, United Kingdom
3 Biostatistics and Epidemiology, Institute of Child Health, University College, London, United Kingdom
4 Molecular Haematology and Cancer Biology Units, Institute of Child Health, University College, London, United Kingdom
* To whom correspondence should be addressed. E-mail: s.j.welham{at}qmul.ac.uk.
Human epidemiological data associating birth weight with adult disease suggests 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 demonstrate 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 orthologue 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 immunolocalised 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 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 maternal diet ingested between conception to 5-6 weeks gestation contributes to the variation in glomerular numbers which are known to occur between healthy and hypertensive populations.
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