title: Genome-wide analysis of gestational gene-environment interactions in the developing kidney.
abstract: The G protein-coupled bradykinin B2 receptor (Bdkrb2) plays an important role in regulation of blood pressure under conditions of excess salt intake. Our previous work has shown that Bdkrb2 also plays a developmental role since Bdkrb2(-/-) embryos, but not their wild-type or heterozygous littermates, are prone to renal dysgenesis in response to gestational high salt intake. Although impaired terminal differentiation and apoptosis are consistent findings in the Bdkrb2(-/-) mutant kidneys, the developmental pathways downstream of gene-environment interactions leading to the renal phenotype remain unknown. Here, we performed genome-wide transcriptional profiling on embryonic kidneys from salt-stressed Bdkrb2(+/+) and Bdkrb2(-/-) embryos. The results reveal significant alterations in key pathways regulating Wnt signaling, apoptosis, embryonic development, and cell-matrix interactions. In silico analysis reveal that nearly 12% of differentially regulated genes harbor one or more Pax2 DNA-binding sites in their promoter region. Further analysis shows that metanephric kidneys of salt-stressed Bdkrb2(-/-) have a significant downregulation of Pax2 gene expression. This was corroborated in Bdkrb2(-/-);Pax2(GFP+/tg) mice, demonstrating that Pax2 transcriptional activity is significantly repressed by gestational salt-Bdkrb2 interactions. We conclude that gestational gene (Bdkrb2) and environment (salt) interactions cooperate to impact gene expression programs in the developing kidney. Suppression of Pax2 likely contributes to the defects in epithelial survival, growth, and differentiation in salt-stressed BdkrB2(-/-) mice.
authors.affiliation: Section of Pediatric Nephrology, Department of Pediatrics, and The Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, Louisiana; and.
authors.forename: Lei
authors.initials: L
authors.lastname: Yan
authors.affiliation: Section of Pediatric Nephrology, Department of Pediatrics, and The Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, Louisiana; and.
authors.forename: Xiao
authors.initials: X
authors.lastname: Yao
authors.affiliation: Department of Medicine, Université Laval, Quebec, Canada.
authors.forename: Dimcho
authors.initials: D
authors.lastname: Bachvarov
authors.affiliation: Section of Pediatric Nephrology, Department of Pediatrics, and The Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, Louisiana; and.
authors.forename: Zubaida
authors.initials: Z
authors.lastname: Saifudeen
authors.affiliation: Section of Pediatric Nephrology, Department of Pediatrics, and The Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, Louisiana; and seldahr@tulane.edu.
authors.forename: Samir S
authors.initials: SS
authors.lastname: El-Dahr
mesh_terms: D000818:Animals; D001665:Binding Sites; D015536:Down-Regulation / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D063990:Gene Ontology; D059647:Gene-Environment Interaction; D017930:Genes, Reporter; D016678:Genome; D007668:Kidney / Q000196:embryology* / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D051762:PAX2 Transcription Factor / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043782:Receptor, Bradykinin B2 / Q000172:deficiency / Q000235:genetics; D015203:Reproducibility of Results; D012965:Sodium Chloride; D013312:Stress, Physiological / Q000235:genetics; D059467:Transcriptome / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
chemical_list: D051762:PAX2 Transcription Factor; D012333:RNA, Messenger; D043782:Receptor, Bradykinin B2; D012965:Sodium Chloride
keywords: bradykinin receptor-knockout mice; gestational salt intake; kidney development; microarray; paired box transcription factor-2