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Ligand-activated Ahr signaling leads to disruption of nephrogenesis and altered Wilms' tumor suppressor mRNA splicing

Oncogene volume 22, pages 2160–2171 (2003)Cite this article

Abstract

The aryl hydrocarbon receptor (Ahr), a member of the large basic helix–loop–helix (bHLH) and PAS homology domain superfamily, is a highly conserved transcriptional regulator involved in mammalian development. In the present study, a murine metanephros organ culture system was employed to evaluate the role of the Ahr signaling in nephrogenesis in vitro. Ahr and Wilms' tumor suppressor (wt1) mRNAs were detected by in situ hybridization and RT–PCR during the course of renal development. Treatment with 3 μ M BaP, a hydrocarbon ligand of Ahr, inhibited glomerulogenesis and branching morphogenesis of metanephric kidneys. Deficits in the epithelialization of mesenchymal cells were evidenced by inhibition of the formation of podocyte foot processes and glomerular basement membranes. Hydrocarbon treatment markedly induced −KTS wt1 splice variants, although total wt1 mRNA levels remained unchanged. A significant decrease in total WT1 protein was observed by both immunocytochemistry and Western analysis in cultures challenged with BaP compared to controls. Comparison of metanephric cultures from Ahr+/+ and Ahr−/− mice showed that Ahr is involved in kidney development, and required for BaP-induced deficits in nephrogenesis. These results indicate that ligand activation of Ahr signaling disrupts nephrogenesis in vitro, and that this response involves modulation of wt1 alternative splicing and post-transcriptional control.

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References

  • Abbott BD . (1995). Toxicology, 105, 365–373.

  • Aswin M, Lasley M, Micholas DH and Andreas S . (1998). Kidney Int., 53, 1512–1518.

  • Avner ED . (1993). Sem. Nephrol., 13, 427–435.

  • Avner ED and Sweeney WE . (1990). Pediatr. Nephrol., 4, 372–377.

  • Barbaux S, Niaudet P, Gubler MC, Grunfeld JP, Jaubert F, Kuttern F, Fekete CN, Souleyreau-Theville N, Thibaud E, Fellous M and McElreavey K . (1997). Nat. Genet., 17, 467–470.

  • Bowes RC, Parrish AR, Steinberg MA, Willet KL, Zhao W, Savas U, Jefcoate CR, Safe SH and Ramos KS (1996). Biochem. Pharmacol., 52, 587–595.

  • Bowes RC and Ramos KS (1994). Toxicol. In Vitro, 8, 1151–1160.

  • Bradford MM . (1976). Anal. Biochem., 72, 248–254.

  • Bruening W and Pelletier J . (1996). J. Biol. Chem., 271, 8646–8654.

  • Cantrell SM, Joy-Schlezinger J, Stegeman JJ, Tillitt DE and Hannink M . (1997). Toxicol. Appl. Pharmacol., 148, 24–34.

  • Carver LA and Bradfield CA . (1997). J. Biol. Chem., 272, 11452–11456.

  • Crews ST and Fan CM . (1999). Curr. Opion. Gen. Dev., 9, 580–587.

  • Dressler GR . (1997). Adv. Nephrol. Necker Hosp., 26, 1–17.

  • Drumond IA, Madden SL, Rohwer NP, Bell GI, Suklhatme VP and Rauscher FI . (1992). Science, 257, 674–678.

  • Gessler M, Konig A and Bruns GA . (1992). Genomics, 12, 807–813.

  • Gutierrez A, Khan ZU, Miralles CP, Mehta AK, Ruano D, Araujo F, Victorica J and De Blas AL . (1997). Mol. Brain Res., 45, 59–70.

  • Haber DA, Sohn RL, Bucker AJ, Pelletier J, Call KM and Housman DE . (1991). Proc. Natl. Acad. Sci. USA, 88, 9618–9622.

  • Habib R, Loirat C, Gubler MC, Niaudet P, Bensam A, Levy M and Broyer M . (1985). Clin. Nephrol., 24, 269–278.

  • Hammes A, Guo JK, Lutsch G, Leheste JR, Landrock D, Siegler U, Gubler MC and Schedl A . (2001). Cell, 106, 319–329.

  • Hewitt SM and Saunders GF . (1996). Anticancer Res., 16, 621–626.

  • Hida M, Omori S and Awazu M . (2002). Kidney Int., 61, 1252–1262.

  • Hundeiker C, Pineau T, Gassar G, Betensky RA, Gleichmann E and Esser C . (1999). Int. J. Immunopharmacol., 21, 841–859.

  • Hushka LJ, Williams JS and Greenlee WF . (1998). Toxicol. Appl. Pharmacol., 152, 200–210.

  • Kafafi SA, Afeefy HY, Said HK and Kafafi AG . (1993). Chem. Res. Toxicol., 6, 328–334.

  • Kim DW, Gazourian L, Quadri SA, Romieu-Mourez R, Sherr DH and Sonenshein GE . (2000). Oncogene, 19, 5498–5506.

  • Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D and Jaenisch R . (1993). Cell, 74, 679–691.

  • Kudoh T, Ishidate T, Nakamura T, Toyoshima K and Akiyama T . (1996). Oncogene, 13, 1431–1439.

  • Lahvis GP, Lindell SL, Thomas RS, McCluskey RS, Murphy C, Glover E, Bentz M, Southard J and Bradfield CA . (2000). Proc. Natl. Acad. Sci. USA, 97, 10442–10447.

  • Laity JH, Chung J, Dyson J and Wright PE . (2000). Biochemistry, 39, 5341–5348.

  • Larsson SH, Charlieu JP, Miyagawa K, Engelkamp D, Rassoulzadegan M, Ross A, Cuzin F, Heyningen V and Hastie ND . (1995). Cell, 81, 391–401.

  • Nebert DW . (1994). Biochem. Pharmacol. 47, 25–37.

  • Peters JM, Narotsky MG, Elizondo G, Fernandez-Salguero PM, Gonzalez FJ and Abbott BD . (1999). Toxicol. Sci., 47, 86–92.

  • Peterson RE, Theobald HM and Kimmel GL . (1993). Crit. Rev. Toxicol., 23, 283–337.

  • Pritchard-Jones K, Flering S, Davidson D, Bickmore W, Porteus D, Gosden C, Bard J, Buckler A, Pelletier J and Housman D . (1990). Nature, 346, 194–197.

  • Renshaw J, King-Underwood L and Pritchard-Jones K . (1997). Genes Chrom. Cancer, 19, 256–266.

  • Ryan G, Steelepperkins V, Morris JF, Rauscher FJ and Dressler GR . (1995). Development, 121, 867–875.

  • Saxon L . (ed). (1987). Organogenesis of the Kidney. Cambridge University Press: Cambridge, UK.

    Book  Google Scholar 

  • Scharnhorst V, Deker P, Vander-EB AJ and Jochemsen AG . (1999). J. Biol. Chem., 274, 23456–23462.

  • Scharnhorst V, Kranenburg O, Van Der EB AJ and Jochemsen AG . (1997). Cell Growth Differ., 8, 133–143.

  • Schmidt JV, Huei-Ting Su GH, Reddy JK, Simon MC and Bradfield CA . (1996). Proc. Natl. Acad. Sci. USA, 93, 6731–6736.

  • Sharma PM, Bowman M, Madden SL, Rauscher FJ and Sukumar S . (1994). Genes Dev., 8, 720–731.

  • Toth T and Takebayashi S . (1996). Nephron, 74, 64–71.

  • Walker C, Rutten F, Yuan X, Pass H, Mew DM and Everitt J . (1994). Cancer Res., 54, 3101–3106.

  • Wang ZY, Masdden SL, Deuel TF and Rauscher FI . (1992). J. Biol. Chem., 267, 21999–22002.

  • Winn LM and Wells PG . (1997). Free Rod. Biol. Med., 22, 607–621.

  • Yeger H, Forget D, Alami J and Williams B . (1996). In Vitro Cell Dev. Biol., 32, 496–504.

  • Zaher H, Fernandez-Salguero PM, Letterio J, Sheikh MS, Fornace AJ, Roberts AB and Gonzalez FJ . (1998). Mol. Pharmacol., 54, 313–321.

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Acknowledgements

We thank Drs Robert C Burghardt and Rola Barhoumi for assistance with electron microscopy and image analysis, and Mr Marc Holderman for assistance with Western blot analysis. Also, we thank Dr Bhagavatula Moorthy for facilitating the acquisition of C57BL/6J Ahr null mice and Dr Cheryl Walker for valuable comments. This study was supported by NIEHS Grants ES04917 and ES09106.

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  1. Center for Environmental and Rural Health, Texas A & M University, College Station, TX, USA

    M Hadi Falahatpisheh & Kenneth S Ramos

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  1. M Hadi Falahatpisheh
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  2. Kenneth S Ramos
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Correspondence to Kenneth S Ramos.

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Hadi Falahatpisheh, M., Ramos, K. Ligand-activated Ahr signaling leads to disruption of nephrogenesis and altered Wilms' tumor suppressor mRNA splicing. Oncogene 22, 2160–2171 (2003). https://doi.org/10.1038/sj.onc.1206238

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