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An efficient and versatile system for acute and chronic modulation of renal tubular function in transgenic mice

Nature Medicine volume 14, pages 979984 (2008) | Download Citation



We describe a transgenic mouse line, Pax8-rtTA, which, under control of the mouse Pax8 promoter, directs high levels of expression of the reverse tetracycline–dependent transactivator (rtTA) to all proximal and distal tubules and the entire collecting duct system of both embryonic and adult kidneys. Using crosses of Pax8-rtTA mice with tetracycline-responsive c-MYC mice, we established a new, inducible model of polycystic kidney disease that can mimic adult onset and that shows progression to renal malignant disease. When targeting the expression of transforming growth factor-β1 to the kidney, we avoided early lethality by discontinuous treatment and successfully established an inducible model of renal fibrosis. Finally, a conditional knockout of the gene encoding tuberous sclerosis complex-1 was achieved, which resulted in the early outgrowth of giant polycystic kidneys reminiscent of autosomal recessive polycystic kidney disease. These experiments establish Pax8-rtTA mice as a powerful tool for modeling renal diseases in transgenic mice.

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  1. 1.

    & Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proc. Natl. Acad. Sci. USA 89, 5547–5551 (1992).

  2. 2.

    et al. Transcriptional activation by tetracyclines in mammalian cells. Science 268, 1766–1769 (1995).

  3. 3.

    et al. Doxycycline-mediated quantitative and tissue-specific control of gene expression in transgenic mice. Proc. Natl. Acad. Sci. USA 93, 10933–10938 (1996).

  4. 4.

    et al. PAX8, a human paired box gene: isolation and expression in developing thyroid, kidney and Wilms' tumors. Development 116, 611–623 (1992).

  5. 5.

    et al. Pax8, a murine paired box gene expressed in the developing excretory system and thyroid gland. Development 110, 643–651 (1990).

  6. 6.

    et al. Exploring the sequence space for tetracycline-dependent transcriptional activators: novel mutations yield expanded range and sensitivity. Proc. Natl. Acad. Sci. USA 97, 7963–7968 (2000).

  7. 7.

    et al. Detection of integrated papillomavirus sequences by ligation-mediated PCR (DIPS-PCR) and molecular characterization in cervical cancer cells. Int. J. Cancer 92, 9–17 (2001).

  8. 8.

    , , & Stringent doxycycline dependent control of Cre recombinase in vivo. Nucleic Acids Res. 30, e134 (2002).

  9. 9.

    Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat. Genet. 21, 70–71 (1999).

  10. 10.

    , & C-myc as an inducer of polycystic kidney disease in transgenic mice. Kidney Int. 39, 665–671 (1991).

  11. 11.

    & Reversible tumorigenesis by MYC in hematopoietic lineages. Mol. Cell 4, 199–207 (1999).

  12. 12.

    et al. Conditional epidermal expression of TGFβ 1 blocks neonatal lethality but causes a reversible hyperplasia and alopecia. Proc. Natl. Acad. Sci. USA 98, 9139–9144 (2001).

  13. 13.

    et al. Conditional tetracycline-regulated expression of TGF-β1 in liver of transgenic mice leads to reversible intermediary fibrosis. Hepatology 37, 1067–1078 (2003).

  14. 14.

    et al. A germ-line Tsc1 mutation causes tumor development and embryonic lethality that are similar, but not identical to, those caused by Tsc2 mutation in mice. Proc. Natl. Acad. Sci. USA 98, 8762–8767 (2001).

  15. 15.

    et al. A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas and up-regulation of p70S6 kinase activity in Tsc1 null cells. Hum. Mol. Genet. 11, 525–534 (2002).

  16. 16.

    et al. A mouse model of cardiac rhabdomyoma generated by loss of Tsc1 in ventricular myocytes. Hum. Mol. Genet. 14, 429–435 (2005).

  17. 17.

    , & Increased blood pressure in transgenic mice expressing both human renin and angiotensinogen in the renal proximal tubule. Am. J. Physiol. Renal Physiol. 286, F965–F971 (2004).

  18. 18.

    , , & A 346–base pair region of the mouse γ-glutamyl transpeptidase type II promoter contains sufficient cis-acting elements for kidney-restricted expression in transgenic mice. J. Biol. Chem. 272, 11959–11967 (1997).

  19. 19.

    et al. Expression of an AQP2 Cre recombinase transgene in kidney and male reproductive system of transgenic mice. Am. J. Physiol. 275, C216–C226 (1998).

  20. 20.

    et al. Expression of green fluorescent protein in the ureteric bud of transgenic mice: a new tool for the analysis of ureteric bud morphogenesis. Dev. Genet. 24, 241–251 (1999).

  21. 21.

    , & Epithelial-specific Cre/lox recombination in the developing kidney and genitourinary tract. J. Am. Soc. Nephrol. 13, 1837–1846 (2002).

  22. 22.

    , & Follicular cells of the thyroid gland require Pax8 gene function. Nat. Genet. 19, 87–90 (1998).

  23. 23.

    & Generating conditional mouse mutants via tetracycline-controlled gene expression. Methods Mol. Biol. 209, 69–104 (2003).

  24. 24.

    & Variability of intercellular spaces between macula densa cells: a transmission electron microscopic study in rabbits and rats. Kidney Int. Suppl. 12, S9–S17 (1982).

  25. 25.

    , & Embedding in epoxy resins for ultrathin sectioning in electron microscopy. Stain Technol. 35, 313–323 (1960).

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This work was supported by Deutsche Forschungsgemeinschaft grants FOR406 (to W.K. and R.K.) and SFB 405 B10 (to H.-J.G.), by Schweizerische Forschungsstiftung Kind und Krebs (O.G.), by Prof. Dr. Karl und Gerhard Schiller-Stiftung (W.K.) and by US National Institutes of Health grants R01-CA85610, R01-CA105102, 3R01CA089305-03S1, NIH/NCI ICMIC P50 and NIH/NCI 1P20 CA112973 (D.W.F.). We thank P. Soriano (Fred Hutchinson Cancer Research Center) for providing Rosa26R mice; F. Zimmermann and S. Dlugosz for DNA microinjection; I. Voehringer, J. Charon-Alvarez, H. Hosser and B. Hahnel for technical assistance; the teams of the animal facilities at Deutsches Krebsforschungszentrum and Interfakultäre Biomedizinische Forschungseinrichtung Heidelberg for animal caretaking; T.P. Sijmonsma for skillful and expert handling of the mice; S. Wang for help with tissue preservation; M. Schorpp-Kistner and C. Gebhardt for expert advice in mouse embryology; R. Nonnenmacher for graphical work; and W.A. Grandy for carefully reading the manuscript.

Author information

Author notes

    • Milena Traykova-Brauch
    • , Kai Schönig
    •  & Oliver Greiner

    These authors contributed equally to this work.


  1. Department of Cellular and Molecular Pathology, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.

    • Milena Traykova-Brauch
    •  & Hermann-Josef Gröne
  2. Department of Molecular Biology, Central Institute of Mental Health, J5, 68159 Mannheim, Germany.

    • Kai Schönig
  3. University Children's Hospital of Zurich, Steinwiesstrasse 75, 8032 Zürich, Switzerland.

    • Oliver Greiner
    • , Felix K Niggli
    •  & Robert Koesters
  4. Department of Immunology, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.

    • Tewfik Miloud
  5. Institute of Human Genetics, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.

    • Anna Jauch
    •  & Robert Koesters
  6. Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.

    • Manja Bode
    •  & Robert Koesters
  7. Center for Clinical Science Research 1105B, 269 Campus Drive, Stanford, California 94305-5166, USA.

    • Dean W Felsher
  8. Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, 306C Life Sciences Building, University Park, Pennsylvania 16801, USA.

    • Adam B Glick
  9. Translational Medicine Division, Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA.

    • David J Kwiatkowski
  10. Zentrum für Molekulare Biologie, University of Heidelberg, Im Neuenheimer Feld 282, 69120, Heidelberg, Germany.

    • Hermann Bujard
  11. Institute of Human Genetics, University of Muenster, Vesaliusweg 12, 48149 Muenster, Germany.

    • Jürgen Horst
  12. Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 220/221, 69120 Heidelberg, Germany.

    • Magnus von Knebel Doeberitz
    •  & Robert Koesters
  13. Department of Anatomy and Developmental Biology, Medical Faculty Mannheim, University of Heidelberg, Ludolf-Krehl-Strasse 13-17, Tridomus C/6, 68167 Mannheim, Germany.

    • Wilhelm Kriz


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Corresponding author

Correspondence to Robert Koesters.

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