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Isolation and Culture of Cells from the Nephrogenic Zone of the Embryonic Mouse Kidney
08:06

Isolation and Culture of Cells from the Nephrogenic Zone of the Embryonic Mouse Kidney

Published on: April 22, 2011

Modulation of biological regulatory networks during nephrogenesis

Kenneth S Ramos1, M Hadi Falahatpisheh, Adrian Nanez

  • 1Department of Biochemistry and Molecular Biology, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, KY 40292, USA. kenneth.ramos@louisville.edu

Drug Metabolism Reviews
|December 6, 2006
PubMed

Insights

Benzo(a)pyrene disrupts kidney development by inhibiting mesenchymal-to-epithelial transition and altering Wilms' tumor suppressor gene (Wt1) splice variants. This study reveals aryl hydrocarbon receptor (Ahr) plays a key role in renal cell differentiation and kidney development.

Area of Science:

  • Developmental biology
  • Toxicology
  • Genetics

Background:

  • Mesenchymal-to-epithelial transition is crucial for renal cell differentiation, forming tubuloepithelial structures.
  • The Wilms' tumor suppressor gene (Wt1) is a master regulator of genetic events in mesenchymal transdifferentiation during nephrogenesis.
  • Benzo(a)pyrene (BaP), a polycyclic aromatic hydrocarbon and renal carcinogen, can disrupt these developmental processes.

Purpose of the Study:

  • To investigate the disruption of nephrogenesis by benzo(a)pyrene (BaP) through aryl hydrocarbon receptor (Ahr) superactivation.
  • To elucidate the molecular mechanisms underlying BaP's inhibition of metanephric cell differentiation and Wt1 splice variants.
  • To establish the role of Ahr in renal cell differentiation and kidney development.

Main Methods:

  • Systems biology approach combining genomics, transcriptomics, and bioinformatics.
  • Analysis of global gene expression responses in murine metanephric cultures exposed to BaP.
  • Boolean network modeling to resolve genetic regulatory networks.

Main Results:

  • BaP exposure inhibits nephron formation by disrupting metanephric cell differentiation.
  • BaP alters the relative abundance of Wt1 splice variants.
  • BaP causes downregulation of Ahr and disrupts downstream Wt1 targets, revealing interactions between Ahr and Wt1.

Conclusions:

  • Aryl hydrocarbon receptor (Ahr) plays a significant role in renal cell differentiation and kidney development.
  • Disruption of Ahr signaling by BaP interferes with critical genetic networks governing nephrogenesis.
  • This study resolves putative molecular interactions between Ahr and Wt1, providing insights into developmental toxicity.

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