title: AHR regulates WT1 genetic programming during murine nephrogenesis.
abstract: Mounting evidence suggests that the blueprint of chronic renal disease is established during early development by environmental cues that dictate alterations in differentiation programming. Here we show that aryl hydrocarbon receptor (AHR), a lig-and-activated basic helix-loop-helix-PAS homology domain transcription factor, disrupts murine renal differentiation by interfering with Wilms tumor suppressor gene (WT1) signaling in the developing kidney. Embryonic kidneys of C57BL/6J Ahr⁻/⁻ mice at gestation d (GD) 14 showed reduced condensation in the nephrogenic zone and decreased numbers of differentiated structures compared with wild-type mice. These deficits correlated with increased expression of the (+) 17aa Wt1 splice variant, decreased mRNA levels of Igf-1 rec., Wnt-4 and E-cadherin, and reduced levels of 52 kDa WT1 protein. AHR knockdown in wild-type embryonic kidney cells mimicked these alterations with notable increases in (+) 17aa Wt1 mRNA, reduced levels of 52 kDa WT1 protein, and increased (+) 17aa 40-kDa protein. AHR downregulation also reduced Igf-1 rec., Wnt-4, secreted frizzled receptor binding protein-1 (sfrbp-1) and E-cadherin mRNAs. In the case of Igf-1 rec. and Wnt-4, genetic disruption was fully reversed upon restoration of cellular Wt1 protein levels, confirming that functional interactions between AHR and Wt1 represent a likely molecular target for renal developmental interference.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Louisville, Kentucky, United States of America.
authors.forename: M Hadi
authors.initials: MH
authors.lastname: Falahatpisheh
authors.forename: Adrian
authors.initials: A
authors.lastname: Nanez
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Ramos
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D065150:Cellular Reprogramming / Q000235:genetics*; D015536:Down-Regulation / Q000235:genetics; D004848:Epithelium / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D007668:Kidney / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D038081:Organogenesis / Q000235:genetics*; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D025721:WT1 Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; D018336:Receptors, Aryl Hydrocarbon; D025721:WT1 Proteins