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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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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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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DOI: https://doi.org/10.1038/nm.1865
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