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Kidney Gene Expression Analysis in a Rat Model of Intrauterine Growth Restriction Reveals Massive Alterations of Coagulation Genes

Laboratoire de Biochimie et de Biologie Moléculaire (C.B.), Hôpitaux La Conception, Assistance Publique-Hôpital de Marseille (AP-HM), and Unité Propre de Recherche de l’Enseignement Supérieur, Equipe d’Accueil 2193 Faculté de Médecine, 13005 Marseille, France; Service de Médecine Néonatale (F.B., U.S.), Hôpital de La Conception, AP-HM, 13005 Marseille, France, Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 608, Université de la Méditerranée, 13284 Marseille, France; Département de Génétique et Développement (F.M., S.T.C., D.V.), Institut Cochin, INSERM Unité (U) 567, Centre National de la Recherche Scientifique UMR 8104, and Faculté de Médecine René Descartes, Université Paris V, 75014 Paris, France; Centre de Formation et de Recherche Expérimental Medico-Chirurgicale (J.-M.F.), Faculté de Médecine, 13385 Marseille, France; INSERM U872 (M.L.-P.), Centre de recherche des Cordeliers, Université René Descartes (Paris 5), 75006 Paris, France; and Institut National de la Recherche Agronomique Department of Animal Genetics (D.V.), 78352 Jouy-en Josas, France

Address all correspondence and requests for reprints to: Daniel Vaiman, Département de Génétique et Développement, Institut Cochin, Institut National de la Santé et de la Recherche Médicale Unité 567, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, and Faculté de Médecine René Descartes, Université Paris V UM 3, 75014 Paris, France. E-mail: vaiman{at}cochin.inserm.fr.

In this study, low birth weight was induced in rats by feeding the dams with a low-protein diet during pregnancy. Kidneys from the fetuses at the end of gestation were collected and showed a reduction in overall and relative weight, in parallel with other tissues (heart and liver). This reduction was associated with a reduction in nephrons number. To better understand the molecular basis of this observation, a transcriptome analysis contrasting kidneys from control and protein-deprived rats was performed, using a platform based upon long isothermic oligonucleotides, strengthening the robustness of the results. We could identify over 1800 transcripts modified more than twice (772 induced and 1040 repressed). Genes of either category were automatically classified according to functional criteria, making it possible to bring to light a large cluster of genes involved in coagulation and complement cascades. The promoters of the most induced and most repressed genes were contrasted for their composition in putative transcription factor binding sites, suggesting an overrepresentation of the AP1R binding site, together with the transcription induction of factors actually binding to this site in the set of induced genes. The induction of coagulation cascades in the kidney of low-birth-weight rats provides a putative rationale for explaining thrombo-endothelial disorders also observed in intrauterine growth-restricted human newborns. These alterations in the kidneys have been reported as a probable cause for cardiovascular diseases in the adult.