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

Abstract

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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Figure 1: Pax8-rtTA–mediated, doxycycline-controlled β-galactosidase expression in adult tissues.
Figure 2: Pax8-rtTA–mediated, doxycycline-controlled β-galactosidase expression in adult renal tubular cells.
Figure 3: Pax8-rtTA–mediated, doxycycline-controlled β-galactosidase expression in embryonic kidney.
Figure 4: Time course of transgene induction in Pax8-rtTA/LC-1–transgenic mice upon doxycycline administration.
Figure 5: Renal disease models.

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References

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  6. Urlinger, S. 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).

    Article  CAS  Google Scholar 

  7. Luft, F. 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).

    Article  CAS  Google Scholar 

  8. Schonig, K., Schwenk, F., Rajewsky, K. & Bujard, H. Stringent doxycycline dependent control of Cre recombinase in vivo. Nucleic Acids Res. 30, e134 (2002).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. Trudel, M., D'Agati, V. & Costantini, F. C-myc as an inducer of polycystic kidney disease in transgenic mice. Kidney Int. 39, 665–671 (1991).

    Article  CAS  Google Scholar 

  11. Felsher, D.W. & Bishop, J.M. Reversible tumorigenesis by MYC in hematopoietic lineages. Mol. Cell 4, 199–207 (1999).

    Article  CAS  Google Scholar 

  12. Liu, X. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  14. Kobayashi, T. 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).

    Article  CAS  Google Scholar 

  15. Kwiatkowski, D.J. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  17. Lavoie, J.L., Lake-Bruse, K.D. & Sigmund, C.D. 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).

    Article  CAS  Google Scholar 

  18. Sepulveda, A.R., Huang, S.L., Lebovitz, R.M. & Lieberman, M.W. 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).

    Article  CAS  Google Scholar 

  19. Nelson, R.D. 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).

    Article  CAS  Google Scholar 

  20. Srinivas, S. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  22. Mansouri, A., Chowdhury, K. & Gruss, P. Follicular cells of the thyroid gland require Pax8 gene function. Nat. Genet. 19, 87–90 (1998).

    Article  CAS  Google Scholar 

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

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  25. Richardson, K.C., Jarett, L. & Finke, E.H. Embedding in epoxy resins for ultrathin sectioning in electron microscopy. Stain Technol. 35, 313–323 (1960).

    Article  CAS  Google Scholar 

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Acknowledgements

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.

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Correspondence to Robert Koesters.

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Supplementary Figs. 1 and 2 and Supplementary Methods (PDF 2382 kb)

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Traykova-Brauch, M., Schönig, K., Greiner, O. et al. An efficient and versatile system for acute and chronic modulation of renal tubular function in transgenic mice. Nat Med 14, 979–984 (2008). https://doi.org/10.1038/nm.1865

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