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Molecular Medicine

, Volume 17, Issue 11–12, pp 1275–1284 | Cite as

AHR Regulates WT1 Genetic Programming during Murine Nephrogenesis

  • M. Hadi Falahatpisheh
  • Adrian Nanez
  • Kenneth S. Ramos
Research Article

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 ligand-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. ln 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.

Notes

Acknowledgments

This study was supported by NIH Grants ES04917, ES012542 and ES014443. The authors wish to thank Steven Potter (Children’s Hospital Medical Center, Cincinnati, OH, USA) for providing the mK3 and mK4 cell lines, Aart G Jochemsen (Leiden University Medical Center, Leiden, The Netherlands) for Wt1 cDNA plasmids and Vilius Stribinskis for helpful discussions. The assistance of Marlene Steffen and Diego Montoya is gratefully acknowledged.

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Copyright information

© The Feinstein Institute for Medical Research 2011

Authors and Affiliations

  • M. Hadi Falahatpisheh
    • 1
  • Adrian Nanez
    • 1
  • Kenneth S. Ramos
    • 1
  1. 1.Department of Biochemistry and Molecular BiologyUniversity of Louisville School of MedicineLouisvilleUSA

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